WO2025024288A1

WO2025024288A1 - Heterocyclic pad4 inhibitors

Info

Publication number: WO2025024288A1
Application number: PCT/US2024/038782
Authority: WO
Inventors: Makonen Belema; John A. Bender; Alyssa H. Antropow; Jason M. Guernon; Alan Xiandong WANG; Daniel L. Cheney
Original assignee: Bristol-Myers Squibb Company
Priority date: 2023-07-21
Filing date: 2024-07-19
Publication date: 2025-01-30

Abstract

The disclosure generally relates to compounds of Formula I, which are inhibitors of PAD4, methods for preparing these compounds, pharmaceutical compositions comprising these compounds and uses of these compounds in the treatment of diseases or disorders associated with PAD4 enzyme activity.

Description

HETEROCYCLIC PAD4 INHIBITORS

CROSS REFERENCE

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63/514,934 filed on July 21^st, 2023, the entire contents of which are hereby incorporated by reference herein.

FIELD

[0002] The disclosure generally relates to substituted heterocyclic compounds, methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and use of these compounds in the treatment of diseases or disorders associated with PAD4 enzyme activity.

INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0003] This application contains a Sequence Listing which has been submitted in .XML format via EFS-WEB and is hereby incorporated by reference in its entirety. Said .XML copy, created on June 19, 2023 is named 055920-606P01US SeqList ST26.xml and is 3 kilobytes in size.

BACKGROUND

[0004] PAD4 (SEQ ID NO: 1) is a member of the peptidylarginine deiminase (PAD) family of enzymes capable of catalysing the citrullination of arginine into citrulline within peptide sequences. PAD4 is responsible for the deimination or citrullination of a variety of proteins in vitro and in vivo, with consequences of diverse functional responses in a variety of diseases (Jones J.E. et al, Curr. Opin. Drug Discov. DeveL, 12(5), (2009), 616-627). Examples of exemplar diseases or disorders include rheumatoid arthritis, diseases with neutrophilic contributions to pathogenesis (for example vasculitis, systemic lupus erythematosus, ulcerative colitis) in addition to oncology indications. PAD4 inhibitors also have wider applicability as tools and therapeutics for human diseases and disorders through epigenetic mechanisms.

[0005] Inhibitors of PAD4 have utility against Rheumatoid Arthritis (RA). RA is an autoimmune disease affecting approximately 1% of the population (Wegner N. et al, Immunol. Rev., 233(1), (2010), 34-54). It is characterized by inflammation of articular joints leading to debilitating destruction of bone and cartilage. A weak genetic association between PAD4 polymorphisms and susceptibility to RA has been suggested, albeit inconsistently, in a number of population studies (Kochi Y. et al, Ann. Rheum. Dis., 70, (2011), 512-515). PAD4 (along with family member PAD2) has been detected in synovial tissue where it is responsible for the deimination of a variety of joint proteins. This process is presumed to lead to a break of tolerance to, and initiation of immune responses to, citrullinated substrates such as fibrinogen, vimentin and collagen in RA joints. These anti-citrullinated protein antibodies (ACPA) contribute to disease pathogenesis and may also be used as a diagnostic test for RA (e.g. the commercially available CCP2 or cyclic citrullinated protein 2 test). In addition, increased citrullination may also offer additional direct contributions to disease pathogenesis through its ability to affect directly the function of several joint and inflammatory mediators (e.g., fibrinogen, anti-thrombin, and multiple chemokines). In a smaller subset of RA patients, anti -PALM antibodies can be measured and may correlate with a more erosive form of the disease.

[0006] PAD4 inhibitors are also useful for the reduction of pathological neutrophil activity in a variety of diseases. Studies suggest that the process of Neutrophil Extracellular Trap (NET) formation, an innate defense mechanism by which neutrophils are able to immobilize and kill pathogens, is associated with histone citrullination and is deficient in a PAD4 knockout mice (Neelil. et al, J. Immunol., 180, (2008), 1895-1902, and Li P. et al, J. Exp. Med., 207(9), (2010), 1853-1862). PALM inhibitors may therefore have applicability for diseases where NET formation in tissues contributes to local injury and disease pathology. Such diseases include, but are not limited to, small vessel vasculitis (Kessenbrock K. et al, Nat. Med., 15(6), (2009), 623-625), systemic lupus erythematosus (Hakkim A. etal, Proc. Natl. Acad. Sci. USA, 107(21), (2010), 9813-9818, and Villanueva E. et al, J. Immunol., 187(1), (2011), 538-52), ulcerative colitis (Savchenko A. et al, Pathol. Int., 61(5), (2011), 290-7), cystic fibrosis, asthma (Dworski R. et al, J. Allergy Clin. Immunol., 127(5), (2011), 1260-6), deep vein thrombosis (Fuchs T. et al, Proc. Natl. Acad. Sci. USA, 107(36), (2010), 15880-5), periodontitis (Vitkov L. et al, Ultrastructural Pathol., 34(1), (2010), 25-30), sepsis (Clark S.R. etal, Nat. Med., 13(4), (2007), 463-9), appendicitis (Brinkmann V. et al, Science, 303, (2004), 1532-5), and stroke. In addition, there is evidence thatNETs may contribute to pathology in diseases affecting the skin, e.g., in cutaneous lupus erythematosis (Villanueva E. et al, J. Immunol., 187(1), (2011), 538-52) and psoriasis (Lin A.M. et al., J. Immunol., 187(1), (2011), 490-500), so a PAD4 inhibitor may show benefit to tackle NET skin diseases, when administered by a systemic or cutaneous route. PAD4 inhibitors may affect additional functions within neutrophils and have wider applicability to neutrophilic diseases.

[0007] Studies have demonstrated efficacy of tool PAD inhibitors (for example, chloroamidine) in a number of animal models of disease, including collagen-induced arthritis (Willis VC. et al, J. Immunol., 186(7), (2011), 4396-4404), dextran sulfate sodium (DSS)-induced experimental colitis (Chumanevich A.A. et al, Am. J. Physiol. Gastrointest. Liver Physiol., 300(6), (2011), G929-G938), spinal cord repair (Lange S. et al, Dev. Biol., 355(2), (2011), 205-14), and experimental autoimmune encephalomyelitis (EAE). The DSS colitis report also demonstrates that chloro-amidine drives apoptosis of inflammatory cells both in vitro and in vivo, suggesting that PAD4 inhibitors may be effective more generally in widespread inflammatory diseases.

[0008] PAD4 inhibitors are also useful in the treatment of cancers (Slack J.L. et al, Cell. Mol. Life Sci., 68(4), (2011), 709-720). Over-expression of PAD4 has been demonstrated in numerous cancers (Chang X. etal, BMC Cancer, 9, (2009), 40). An anti-proliferative role has been suggested for PAD4 inhibitors from the observation that PAD4 citrullinates arginine residues in histones at the promoters of p53 -target genes such as p21, which are involved in cell cycle arrest and induction of apoptosis (Li P. et al, Mol. Cell Biol., 28(15), (2008), 4745-4758).

[0009] The aforementioned role of PAD4 in deiminating arginine residues in histones may be indicative of a role for PAD4 in epigenetic regulation of gene expression. PAD4 is the primary PAD family member observed to be resident in the nucleus as well as the cytoplasm. Early evidence that PAD4 may act as a histone demethyliminase as well as a deiminase is inconsistent and unproven. However, it may reduce histone arginine methylation (and hence epigenetic regulation associated with this mark) indirectly via depletion of available arginine residues by conversion to citrulline. PAD4 inhibitors are useful as epigenetic tools or therapeutics for affecting expression of varied target genes in additional disease settings. Through such mechanisms, PAD4 inhibitors may also be effective in controlling citrullination levels in stem cells and may therefore therapeutically affect the pluripotency status and differentiation potential of diverse stem cells including, but not limited to, embryonic stem cells, neural stem cells, haematopoietic stem cells and cancer stem cells. Accordingly, there remains an unmet need to identify and develop PAD4 inhibitors for the treatment of PAD4-mediated diseases or disorders. SUMMARY [0010] The present disclosure relates to compounds of Formula I: I and pharmaceutically acceptable salts, isomers, enantiomers, or tautomers thereof, wherein X₁ and X₂ are each independently CR₈ or N; Y is selected from -(CR9R10)p–, –O–(CR9R10)p-, –(CR9R10)p–O–(CH2)m-, –(CR9R10)p–O–(CH2)m– O–CH2–, and –(CR9R10)p–O–(CH2)m–O–; R₁ is independently –CH(NHR₇)-(C₁-C₃alkyl) or a 4- to 8-membered heterocyclyl containing at least one heteroatom selected from the group consisting of N, O, or S, wherein the alkyl or heterocyclyl is optionally substituted with one or more R11; R₂ is independently H, or C₁-C₄ alkyl; R₃ are independently H, halogen, or C₁-C₄ alkyl; R4 is independently hydrogen, C1–C4 alkyl, or C1–C4 haloalkyl; R₅ and R₆ are independently selected from H, halogen, C₁–C₄ alkyl, C₁–C₄ alkoxy, C₁–C₄ haloalkyl, heteroaryl, and aryl; wherein the heteroaryl, or aryl is optionally substituted with one or more halogen or C1-C6 alkoxy, or R5 and R6 together with the intervening atoms, form a C3-C6 cycloalkyl or 4- to 8-membered heterocyclyl, or R5, R6, and R9 together with the intervening and adjacent atoms, form a C3-C6 cycloalkyl, 4- to 8- membered heterocyclyl, a heteroaryl, or an aryl, wherein the cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more R₁₂; each R7 is independently selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl; each R₈ is independently selected from H, halogen, C₁–C₄ alkyl, C₁–C₄ haloalkyl, and C₁–C₄ alkoxy, each R9 is independently H, halogen, C1-C4 alkyl, or C3-C4 carbocyclyl; each R10 is independently H, halogen, or C1-C4 alkyl; each R₁₁ is independently selected from H, halogen, C₁–C₆ alkyl, and C₁–C₆ alkoxy; each R12 is independently selected from H, halogen, -OH, -NH2, -CN, C1–C6 alkyl, C1–C4 alkoxy, C1–C4 haloalkoxy, C1–C4 haloalkyl, and C3–C4 cycloalkyl, 3- to 10-membered heterocyclyl, heteroaryl, and C₆–C₁₀ aryl; L is a bond or –CH2–; m is an integer selected from 1, 2, and 3; and p is an integer selected from 2, 3, 4, 5, and 6. [0011] In another aspect, the present disclosure provides a pharmaceutical composition comprising at least one compound of Formula I, or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof, and one or more pharmaceutically acceptable carriers, excipients, or vehicles In some aspects, a provided pharmaceutical composition is suitable for oral, parenteral, mucosal, transdermal, or topical administration. [0012] In another aspect, the present disclosure provides a method of treating a disease or a disorder associated with PAD4 enzyme activity, comprising administering to a subject in need of such treatment, a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof. [0013] In another aspect, the present disclosure provides a method of treating diseases or disorders associated with PAD4 enzyme activity, comprising administering to a subject in need of such treatment, a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof. Such disorders or conditions include, among others, rheumatoid arthritis, vasculitis, systemic lupus erythematosus, and ulcerative colitis. [0014] Another aspect of the present disclosure is directed to a method of treating or preventing a condition disclosed herein in a subject in need thereof. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0015] Another aspect of the present disclosure relates to compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a condition disclosed herein.

[0016] Another aspect of the present disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of a condition disclosed herein.

[0017] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in Examples 1-44).

[0018] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.

[0019] In some aspects, the present disclosure provides a method of preparing a compound, comprising one or more steps described herein.

DETAILED DESCRIPTION

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed present disclosure. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control. Definitions

[0021] Compounds of this disclosure include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0022] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “carbocyclic”, “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, zz-butyl, sec-butyl, isobutyl, tert-butyl, and the like.

[0023] In some embodiments, “carbocyclic” (or “cycloaliphatic” or “carbocycle” or “cycloalkyl”) refers to a C3-C8 hydrocarbon, which may be monocyclic or multicyclic, that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. The rings of multi-ring carbocyclics may exist as fused, bridged and/or joined through one or more spiro union to 1 or 2 aromatic cycloalkyl or heterocyclic rings. Typical, non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl, and the like. [0024] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2Z/-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl)). In some embodiments, an oxidized form of sulfur includes S=O and S(=O)2.

[0025] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0026] The term “halogen” means F, Cl, Br, or I.

[0027] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,”

“aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present disclosure, “aryl” refers to an aromatic ring system and exemplary groups include phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0028] The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 K electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Exemplary heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Examplary groups include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4/f-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0029] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3, 4-di hydro-27/ pyrrolyl), NH (as in pyrrolidinyl), or ⁺NR (as in /V substituted pyrrolidinyl).

[0030] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 37/-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0031] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined. [0032] As described herein, compounds of the disclosure may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure (e.g., refers to at least ; and refers to at least , , or ). Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. [0033] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH₂)_0–4R ^; –(CH₂)_0–4OR ^; -O(CH₂)_0-4R^o, –O– (CH₂)_0–4C(O)OR°; –(CH₂)_0–4CH(OR ^)₂; –(CH₂)_0–4SR ^; –(CH₂)_0–4Ph, which may be substituted with R°; –(CH₂)_0–4O(CH₂)_0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R ^)2; –(CH2)0–4N(R ^)C(O)R º; –N(R ^)C(S)R ^; –(CH2)0–4N(R ^)C(O)NR ^2; -N(R ^)C(S)NR ^2; –(CH2)0–4N(R ^)C(O)OR ^; –N(R º)N(R ^)C(O)R ^; -N(R ^)N(R ^)C(O)NR ^2; -N(R ^)N(R ^)C(O)OR ^; –(CH2)0–4C(O)R ^; –C(S)R ^; –(CH2)0–4C(O)OR ^; –(CH2)0–4C(O)SR ^; -(CH2)0–4C(O)OSiR ^3; –(CH2)0–4OC(O)R ^; –OC(O)(CH2)0–4SR°; –(CH2)0–4SC(O)R ^; –(CH2)0–4C(O)NR ^2; –C(S)NR ^2; –C(S)SR°; –SC(S)SR°, -(CH2)0–4OC(O)NR ^2; -C(O)N(OR ^)R ^; –C(O)C(O)R ^; –C(O)CH2C(O)R ^; –C(NOR ^)R ^; -(CH2)0–4SSR ^; –(CH2)0–4S(O)2R ^; –(CH2)0–4S(O)2OR ^; –(CH2)0–4OS(O)2R ^; –S(O)2NR ^2; -(CH2)0–4S(O)R ^; -N(R°)S(O)₂NR°₂; -N(R°)S(0)₂R^O; -N(OR°)R°; -C(NH)NR^O ₂; -P(O)₂R^O; -P(O)R^O ₂; -OP(O)R^O ₂; -OP(O)(OR^O)₂; SiR°3; -(C1-4 straight or branched alkylene)O-N(R°)₂; or -(C 1-4 straight or branched alkylene)C(O)O-N(R°)₂, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH₂Ph, -0(CH₂)o iPh, -CH₂-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12- membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0034] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH₂)_{0 2}R*, -(haloR*), -(CH₂)_{0 2}OH, -(CH₂)_{0 2}OR’, -(CH₂)o-₂CH(OR*)₂; -O(haloR’), -CN, -N₃, -(CH₂)O-₂C(0)R*, -(CH₂)_{O 2}C(O)OH, -(CH₂)O ₂C(O)OR*, -(CH₂)O ₂SR’, -(CH₂)O ₂SH, -(CH₂)O ₂NH₂, -(CH₂)O ₂NHR’, -(CH₂)O ₂NR’₂, -NO₂, -SiR%, -OSiR%, -C(O)SR* - (C straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic, -CH₂Ph, -0(CH₂)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0035] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0 (“oxo”), =S, =NNR*₂, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)₂R*, =NR*, =N0R*, -O(C(R*₂))₂ 3O-, or -S(C(R*₂))₂ _₃S- wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*₂)₂-3O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0036] Suitable substituents on the aliphatic group of R* include halogen, -

R*, -(haloR*), -OH,

-OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH₂, -NHR*, -NR*₂, or -NO₂, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH₂Ph, 0(CH₂)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R\ -NR^f ₂, -C(O)R^f, -C(O)OR^t, -C(O)C(O)R⁺, -

C(O)CH₂C(O)R^t, -S(O)₂R^t, -SCO^NR^, -C(S)NR^f ₂, -C(NH)NR^f ₂, or -NCR^SCO)^; wherein each R¹' is independently hydrogen, Ci-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^:, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] Suitable substituents on the aliphatic group of R^: are independently halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH₂, -NHR*, -NR*₂, or -NO₂, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CH₂Ph, -0(CH₂)o iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0039] The term “subject” as used herein refers to and includes any human or non-human organism that could potentially benefit from treatment with a PAD4 inhibitor. Exemplary subjects include humans and animals.

[0040] The terms “treating” or “treatment” as used herein refer to and include treatment of a disease-state in a subject, for example in a human or animal, and include: (a) inhibiting the disease-state, i.e., arresting it’s development; (b) relieving the disease-state, i.e., causing regression of the disease state; and/or (c) preventing the disease-state from occurring in a subject. [0041] The terms “preventing” or “prevention” as used herein refer to and include preventive treatment (i.e. prophylaxis and/or risk reduction) of a subclinical disease-state in a subject, for example in a human or animal, aimed at reducing the probability of the occurrence of a clinical disease-state. Subjects may be selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population. “Prophylaxis” therapies can be divided into (a) primary prevention, and (b) secondary prevention. Primary prevention is defined as treatment in a subject that has not yet presented with a clinical disease state, whereas secondary prevention is defined as preventing a second occurrence of the same or similar clinical disease state.

[0042] As used herein, a “therapeutically effective amount” means an amount of a substance (e.g., a therapeutic agent, composition, and/or formulation) that elicits a desired biological response. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered as part of a dosing regimen to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat, diagnose, prevent, and/or delay the onset of the disease, disorder, and/or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of a provided compound in a formulation to treat a disease, disorder, and/or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and/or reduces incidence of one or more symptoms or features of the disease, disorder, and/or condition. In some embodiments, a “therapeutically effective amount” is at least a minimal amount of a provided compound, or composition containing a provided compound, which is sufficient for treating one or more symptoms of an MK2-mediated disesase or disorder. The term “therapeutically effective amount” refers to and includes an amount of a compound or a composition according to the disclosure that is effective when administered alone or in combination to prevent or treat the disease or disorder associated with PAD4 enzyme activity. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the preventive or therapeutic effect, whether administered in combination, serially, or simultaneously.

[0043] A “pharmaceutically acceptable carrier” refers to media generally accepted in the art for the delivery of biologically active agents to humans and/or animals. Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include, without limitation, the type and nature of the active agent being formulated, the subject to which the agent-containing composition is to be administered, the intended route of administration of the compound or composition, and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Typical, non-limiting examples of such carriers include diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents, perfuming agents, anti-bacterial agents, anti-fungal agents, lubricating agents, dispensing agents, coating agents, and the like. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Allen, L. K, Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

[0044] The present disclosure is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (symbol D or ²H) and tritium (symbol T or ³H). For example, a methyl group may be represented by CH3 or CD3. Isotopes of carbon include ¹³C and ¹⁴C. Isotopically-labeled compounds of the disclosure can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[0045] The compound of Formula I forms salts which are also within the scope of this disclosure. Reference to a compound of the Formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, when a compound of Formula I contains both a basic moiety and an acidic moiety, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein. Pharmaceutically acceptable salts include those generally acceptable in the art of pharmaceutical sciences for administration in a subject, including humans and animals. In general, the pharmaceutically acceptable salts are non-toxic and physiologically acceptable salts. Salts of the compounds according to the disclosure may be formed, for example, by reacting the compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0046] The compounds of Formula I which contain a basic moiety may form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2- naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3 -phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.

[0047] The compounds of Formula I which contain an acidic moiety may form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehy droabietyl)- ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quatemized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.

[0048] The disclosure encompasses compounds of Formula I, or pharmaceutically acceptable salts thereof, methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and use of these compounds in the treatment of diseases or disorders associated with PAD4 enzyme activity.

[0049] In some embodiments, the present disclosure provides a compound of formula I:

I, or pharmaceutically acceptable salts thereof, wherein each of L, Xi, X2, Y, Ri, R2, R3, R4, Rs, Re and R7 is as defined and described herein.

[0050] In some embodiments, the present disclosure provides a compound selected from a compound of any of Formulae la, la-1, la-2, la-3, la-4, and la-5: la,

Ia-2, la-5, or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof; wherein A is C3-C8 cycloalkyl, a 3- to 8-membered heterocyclyl, aryl, or heteroaryl;

X₃ is CH₂, NH, O, or S; and r is an integer from 1 to 3.

[0051] In some embodiments, the present disclosure provides a compound selected from a compound of any of Formulae lb, Ib-1, Ib-2, Ib-3, Ib-4, and Ib-5:

or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof; wherein A is C3-C8 cycloalkyl, a 3- to 8-membered heterocyclyl, aryl, or heteroaryl.

[0052] In some embodiments, the present disclosure provides a compound selected from a compound of any of Formulae Ic, Ic-1, Ic-2, Ic-3, Ic-4, and Ic-5:

or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof; wherein A is Ca-Cs cycloalkyl, a 3- to 8-membered heterocyclyl, aryl, or heteroaryl.

[0053] In some embodiments, the present disclosure provides a compound selected from a compound of any of Formulae Id, le, and If:

Id, Ie, If, or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof; wherein A is C3-C8 cycloalkyl, a 3- to 8-membered heterocyclyl, aryl, or heteroaryl; X₃ is CH₂, NH, O, or S; and r is an integer from 1 to 3. [0054] In some embodiments, X1 is selected from CR8 or N. In some embodiments of any Formulae described herein, X1 is CR8. In some embodiments of any Formulae described herein, X₁ is N. [0055] In some embodiments, X2 is selected from CR8 or N. In some embodiments of any Formulae described herein, X2 is CR8. In some embodiments of any Formulae described herein, X₂ is N. [0056] In some embodiments, Y is selected from -(CR9R10)p–, –O–(CR9R10)p-, – (CR9R10)p–O–(CH2)m-, –(CR9R10)p–O–(CH2)m–O–CH2–, and –(CR9R10)p–O–(CH2)m–O–. In some embodiments of any Formulae described herein, Y is -(CR9R10)p–. In some embodiments of any Formulae described herein, Y is –O–(CR₉R₁₀)_p-. In some embodiments of any Formulae described herein, Y is –(CR₉R₁₀)_p–O–(CH₂)_m-. In some embodiments of any Formulae described herein, Y is –(CR9R10)p–O–(CH2)m–O–CH2–. In some embodiments of any Formulae described herein, Y is –(CR9R10)p–O–(CH2)m–O–. [0057] In some embodiments, R₁ is –CH(NHR₇)-(C₁-C₃ alkyl) or a 4- to 8-membered heterocycle containing at least one heteroatom selected from the group consisting of N, O, or S, wherein the alkyl or heterocycle is optionally substituted with one or more R11. In some embodiments of any Formulae described herein, R₁ is –CH(NHR₇)-(C₁-C₃ alkyl). In some embodiments of any Formulae described herein, where R1 is –CH(NHR7)-(C1-C3 alkyl), the C1- C3 alkyl is substituted with one or more R11. In some embodiments of any Formulae described herein, R₁ is a 4- to 8-membered heterocycle containing at least one heteroatom. In some embodiments of any Formulae described herein the heteroatom is selected from the group consisting of N, O, or S. In some embodiments of any Formulae described herein the heteroatom is N. In some embodiments of any Formulae described herein the heteroatom is O. In some embodiments of any Formulae described herein the heteroatom is S. In some embodiments of any Formulae described herein, the 4- to 8-membered heterocycle containing at least one heteroatom is substituted with one or more R11. [0058] In some embodiments, R₂ is selected from H, and C₁-C₄ alkyl. In some embodiments of any Formulae described herein, R2 is H. In some embodiments of any Formulae described herein, R2 is C1-C4 alkyl. In some embodiments of any Formulae described herein, R2 is C₁-C₃ alkyl. In some embodiments of any Formulae described herein, R₂ is C₁-C₂ alkyl. In some embodiments of any Formulae described herein, R₂ is C₁ alkyl. [0059] As defined generally above, R3 is selected from H, halogen, and C1-C4 alkyl. In some embodiments of any Formulae described herein, R3 is H. In some embodiments of any Formulae described herein, R₃ is halogen. In some embodiments of any Formulae described herein, R3 is C1-C4 alkyl. In some embodiments of any Formulae described herein, R3 is C1-C3 alkyl. In some embodiments of any Formulae described herein, R3 is C1-C2 alkyl. In some embodiments of any Formulae described herein, R₃ is C₁ alkyl. [0060] In some embodiments, R4 is selected from hydrogen, C1-C4 alkyl or C1-C4 haloalkyl. In some embodiments of any Formulae described herein, R4 is hydrogen. In some embodiments of any Formulae described herein, R4 is C1–C4 alkyl. In some embodiments of any Formulae described herein, R₄ is C₁–C₃ alkyl. In some embodiments of any Formulae described herein, R₄ is C₁–C₂ alkyl. In some embodiments of any Formulae described herein, R₄ is C₁ alkyl. In some embodiments of any Formulae described herein, R4 is C2 alkyl. In some embodiments of any Formulae described herein, R4 is C3 alkyl. In some embodiments of any Formulae described herein, R₄ is C₄ alkyl. In some embodiments of any Formulae described herein, R₄ is C₁–C₄ haloalkyl. In some embodiments of any Formulae described herein, R4 is C1–C3 haloalkyl. In some embodiments of any Formulae described herein, R4 is C1–C2 haloalkyl. In some embodiments of any Formulae described herein, R₄ is C₁ haloalkyl. In some embodiments of any Formulae described herein, R4 is C2 haloalkyl. In some embodiments of any Formulae described herein, R4 is C3 haloalkyl. In some embodiments of any Formulae described herein, R4 is C4 haloalkyl. [0061] In some embodiments, R₅ is selected from H, halogen, C₁–C₄ alkyl, C₁–C₄ alkoxy, C1–C4 haloalkyl, heteroaryl, or aryl; where the heteroaryl, or aryl is optionally substituted with one or more halogen, or C1–C6 alkoxy. In some embodiments of any Formulae described herein, R₅ is H. In some embodiments of any Formulae described herein, R₅ is halogen. In some embodiments of any Formulae described herein, R5 is C1–C4 alkyl. In some embodiments of any Formulae described herein, R5 is C1–C3 alkyl. In some embodiments of any Formulae described herein, R₅ is C₁–C₂ alkyl. In some embodiments of any Formulae described herein, R₅ is C₁ alkyl. In some embodiments of any Formulae described herein, R5 is C2 alkyl. In some embodiments of any Formulae described herein, R5 is C3 alkyl. In some embodiments of any Formulae described herein, R₅ is C₄ alkyl. In some embodiments of any Formulae described herein, R₅ is C₁–C₄ alkoxy. In some embodiments of any Formulae described herein, R₅ is C₁–C₃ alkoxy. In some embodiments of any Formulae described herein, R5 is C1–C2 alkoxy. In some embodiments of any Formulae described herein, R5 is C1 alkoxy. In some embodiments of any Formulae described herein, R₅ is C₁–C₄ haloalkyl. In some embodiments of any Formulae described herein, R5 is C1–C3 haloalkyl. In some embodiments of any Formulae described herein, R5 is C1–C2 haloalkyl. In some embodiments of any Formulae described herein, R5 is C1 haloalkyl. In some embodiments of any Formulae described herein, R₅ is C₂ haloalkyl. In some embodiments of any Formulae described herein, R5 is C3 haloalkyl. In some embodiments of any Formulae described herein, R5 is C4 haloalkyl. In some embodiments of any Formulae described herein, R5 is heteroaryl. In some embodiments of any Formulae described herein, R5 is aryl. In some embodiments of any Formulae described herein, where R5 is heteroaryl or aryl, the heteroaryl, or aryl is substituted with one or more halogen. In some embodiments of any Formulae described herein, where Rs is heteroaryl or aryl, the heteroaryl, or aryl is substituted with one or more Ci- Ce alkoxy. In some embodiments of any Formulae described herein, Rs is heteroaryl, wherein the heteroaryl is substituted with one or more halogen. In some embodiments of any Formulae described herein, Rs is heteroaryl, wherein the heteroaryl is substituted with one or more Ci-Ce alkoxy. In some embodiments of any Formulae described herein, Rs is heteroaryl, wherein the heteroaryl is substituted with one or more C1-C5 alkoxy. In some embodiments of any Formulae described herein, Rs is heteroaryl, wherein the heteroaryl is substituted with one or more C1-C4 alkoxy. In some embodiments of any Formulae described herein, Rs is heteroaryl, wherein the heteroaryl is substituted with one or more C1-C3 alkoxy. In some embodiments of any Formulae described herein, Rs is heteroaryl, wherein the heteroaryl is substituted with one or more C1-C2 alkoxy. In some embodiments of any Formulae described herein, Rs is heteroaryl, wherein the heteroaryl is substituted with one or more Ci alkoxy. In some embodiments of any Formulae described herein, Rs is heteroaryl, wherein the heteroaryl is substituted with one or more C2 alkoxy. In some embodiments of any Formulae described herein, Rs is heteroaryl, wherein the heteroaryl is substituted with one or more C3 alkoxy. In some embodiments of any Formulae described herein, Rs is heteroaryl, wherein the heteroaryl is substituted with one or more C4 alkoxy. In some embodiments of any Formulae described herein, Rs is heteroaryl, wherein the heteroaryl is substituted with one or more Cs alkoxy. In some embodiments of any Formulae described herein, Rs is heteroaryl, wherein the heteroaryl is substituted with one or more Ce alkoxy. In some embodiments of any Formulae described herein, Rs is aryl, wherein the aryl is substituted with one or more halogen. In some embodiments of any Formulae described herein, Rs is aryl, wherein the aryl is substituted with one or more Ci-Ce alkoxy. In some embodiments of any Formulae described herein, Rs is aryl, wherein the aryl is substituted with one or more Ci- Cs alkoxy. In some embodiments of any Formulae described herein, Rs is aryl, wherein the aryl is substituted with one or more C1-C4 alkoxy. In some embodiments of any Formulae described herein, Rs is aryl, wherein the aryl is substituted with one or more C1-C3 alkoxy. In some embodiments of any Formulae described herein, Rs is aryl, wherein the aryl is substituted with one or more C1-C2 alkoxy. In some embodiments of any Formulae described herein, Rs is aryl, wherein the aryl is substituted with one or more Ci alkoxy. In some embodiments of any Formulae described herein, R5 is aryl, wherein the aryl is substituted with one or more C2 alkoxy. In some embodiments of any Formulae described herein, R5 is aryl, wherein the aryl is substituted with one or more C3 alkoxy. In some embodiments of any Formulae described herein, R5 is aryl, wherein the aryl is substituted with one or more C4 alkoxy. In some embodiments of any Formulae described herein, R5 is aryl, wherein the aryl is substituted with one or more C5 alkoxy. In some embodiments of any Formulae described herein, R5 is aryl, wherein the aryl is substituted with one or more Ce alkoxy.

[0062] In some embodiments, Re is selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, heteroaryl, or aryl; where the heteroaryl, or aryl is optionally substituted with one or more halogen, or Ci-Ce alkoxy. In some embodiments of any Formulae described herein, Re is H. In some embodiments of any Formulae described herein, Re is halogen. In some embodiments of any Formulae described herein, Re is C1-C4 alkyl. In some embodiments of any Formulae described herein, Re is C1-C3 alkyl. In some embodiments of any Formulae described herein, Re is C1-C2 alkyl. In some embodiments of any Formulae described herein, Re is Ci alkyl. In some embodiments of any Formulae described herein, Re is C2 alkyl. In some embodiments of any Formulae described herein, Re is C3 alkyl. In some embodiments of any Formulae described herein, Re is C4 alkyl. In some embodiments of any Formulae described herein, Re is C1-C4 alkoxy. In some embodiments of any Formulae described herein, Re is C1-C3 alkoxy. In some embodiments of any Formulae described herein, Re is C1-C2 alkoxy. In some embodiments of any Formulae described herein, Re is Ci alkoxy. In some embodiments of any Formulae described herein, Re is C1-C4 haloalkyl. In some embodiments of any Formulae described herein, Re is C1-C3 haloalkyl. In some embodiments of any Formulae described herein, Re is C1-C2 haloalkyl. In some embodiments of any Formulae described herein, Re is Ci haloalkyl. In some embodiments of any Formulae described herein, Re is C2 haloalkyl. In some embodiments of any Formulae described herein, Re is C3 haloalkyl. In some embodiments of any Formulae described herein, Re is C4 haloalkyl. In some embodiments of any Formulae described herein, Re is heteroaryl. In some embodiments of any Formulae described herein, Re is aryl. In some embodiments of any Formulae described herein, where Re is heteroaryl or aryl, the heteroaryl, or aryl is substituted with one or more halogen. In some embodiments of any Formulae described herein, where Re is heteroaryl or aryl, the heteroaryl, or aryl is substituted with one or more Ci- Ce alkoxy. In some embodiments of any Formulae described herein, Re is heteroaryl, wherein the heteroaryl is substituted with one or more halogen. In some embodiments of any Formulae described herein, Re is heteroaryl, wherein the heteroaryl is substituted with one or more Ci-Ce alkoxy. In some embodiments of any Formulae described herein, Re is heteroaryl, wherein the heteroaryl is substituted with one or more C1-C5 alkoxy. In some embodiments of any Formulae described herein, Re is heteroaryl, wherein the heteroaryl is substituted with one or more C1-C4 alkoxy. In some embodiments of any Formulae described herein, Re is heteroaryl, wherein the heteroaryl is substituted with one or more C1-C3 alkoxy. In some embodiments of any Formulae described herein, Re is heteroaryl, wherein the heteroaryl is substituted with one or more C1-C2 alkoxy. In some embodiments of any Formulae described herein, Re is heteroaryl, wherein the heteroaryl is substituted with one or more Ci alkoxy. In some embodiments of any Formulae described herein, Re is heteroaryl, wherein the heteroaryl is substituted with one or more C2 alkoxy. In some embodiments of any Formulae described herein, Re is heteroaryl, wherein the heteroaryl is substituted with one or more C3 alkoxy. In some embodiments of any Formulae described herein, Re is heteroaryl, wherein the heteroaryl is substituted with one or more C4 alkoxy. In some embodiments of any Formulae described herein, Re is heteroaryl, wherein the heteroaryl is substituted with one or more C5 alkoxy. In some embodiments of any Formulae described herein, Re is heteroaryl, wherein the heteroaryl is substituted with one or more Ce alkoxy. In some embodiments of any Formulae described herein, Re is aryl, wherein the aryl is substituted with one or more halogen. In some embodiments of any Formulae described herein, Re is aryl, wherein the aryl is substituted with one or more Ci-Ce alkoxy. In some embodiments of any Formulae described herein, Re is aryl, wherein the aryl is substituted with one or more Ci- C5 alkoxy. In some embodiments of any Formulae described herein, Re is aryl, wherein the aryl is substituted with one or more C1-C4 alkoxy. In some embodiments of any Formulae described herein, Re is aryl, wherein the aryl is substituted with one or more C1-C3 alkoxy. In some embodiments of any Formulae described herein, Re is aryl, wherein the aryl is substituted with one or more C1-C2 alkoxy. In some embodiments of any Formulae described herein, Re is aryl, wherein the aryl is substituted with one or more Ci alkoxy. In some embodiments of any Formulae described herein, Re is aryl, wherein the aryl is substituted with one or more C2 alkoxy. In some embodiments of any Formulae described herein, Re is aryl, wherein the aryl is substituted with one or more C3 alkoxy. In some embodiments of any Formulae described herein, Re is aryl, wherein the aryl is substituted with one or more C4 alkoxy. In some embodiments of any Formulae described herein, R₆ is aryl, wherein the aryl is substituted with one or more C₅ alkoxy. In some embodiments of any Formulae described herein, R₆ is aryl, wherein the aryl is substituted with one or more C6 alkoxy. [0063] In some embodiments of any Formulae described herein, R5 and R6 together with the intervening atoms, form a C₃-C₆ cycloalkyl or 4- to 8-membered heterocyclyl. In some embodiments of any Formulae described herein, R5 and R6 together with the intervening atoms, form a C3-C6 cycloalkyl. In some embodiments of any Formulae described herein, R5 and R6 together with the intervening atoms, form a C₃-C₅ cycloalkyl. In some embodiments of any Formulae described herein, R5 and R6 together with the intervening atoms, form a C3-C4 cycloalkyl. In some embodiments of any Formulae described herein, R5 and R6 together with the intervening atoms, form a C₃ cycloalkyl. In some embodiments of any Formulae described herein, R₅ and R₆ together with the intervening atoms, form a 4- to 8-membered heterocyclyl. In some embodiments of any Formulae described herein, R5 and R6 together with the intervening atoms, form a 4- to 7-membered heterocyclyl. In some embodiments of any Formulae described herein, R₅ and R₆ together with the intervening atoms, form a 4- to 6-membered heterocyclyl. In some embodiments of any Formulae described herein, R5 and R6 together with the intervening atoms, form a 4- to 5-membered heterocyclyl. In some embodiments of any Formulae described herein, R₅ and R₆ together with the intervening atoms, form a 4-membered heterocyclyl. [0064] In some embodiments, each R7 is independently selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl. In some embodiments of any Formulae described herein, at least one R7 is H. In some embodiments of any Formulae described herein, at least one R₇ is C₁-C₄ alkyl. In some embodiments of any Formulae described herein, at least one R₇ is C₁-C₃ alkyl. In some embodiments of any Formulae described herein, at least one R7 is C1-C2 alkyl. In some embodiments of any Formulae described herein, at least one R7 is C1 alkyl. In some embodiments of any Formulae described herein, at least one R₇ is C₂ alkyl. In some embodiments of any Formulae described herein, at least one R7 is C3 alkyl. In some embodiments of any Formulae described herein, at least one R7 is C3-C4 cycloalkyl. In some embodiments of any Formulae described herein, at least one R₇ is C₃ cycloalkyl. In some embodiments of any Formulae described herein, at least one R7 is C4 cycloalkyl. In some embodiments of any Formulae described herein, at least one R7 is cyclopropyl. [0065] As defined generally above, each Rs is independently selected from H, halogen, - C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy. In some embodiments of any Formulae described herein, at least one Rs is independently selected from halogen, alkoxy and alkyl. In some embodiments of any Formulae described herein, at least one Rs is H. In some embodiments of any Formulae described herein, at least one Rs is halogen. In some embodiments of any Formulae described herein, at least one Rs is C1-C4 alkyl. In some embodiments of any Formulae described herein, at least one Rs is C1-C3 alkyl. In some embodiments of any Formulae described herein, at least one Rs is C1-C2 alkyl. In some embodiments of any Formulae described herein, at least one Rs is Ci alkyl. In some embodiments of any Formulae described herein, at least one Rs is C2 alkyl. In some embodiments of any Formulae described herein, at least one Rs is C3 alkyl. In some embodiments of any Formulae described herein, at least one Rs is C4 alkyl. In some embodiments of any Formulae described herein, at least one Rs is C1-C4 haloalkyl. In some embodiments of any Formulae described herein, at least one Rs is C1-C3 haloalkyl. In some embodiments of any Formulae described herein, at least one Rs is C1-C2 haloalkyl. In some embodiments of any Formulae described herein, at least one Rs is Ci haloalkyl. In some embodiments of any Formulae described herein, at least one Rs is C2 haloalkyl. In some embodiments of any Formulae described herein, at least one Rs is C3 haloalkyl. In some embodiments of any Formulae described herein, at least one Rs is C4 haloalkyl. In some embodiments of any Formulae described herein, at least one Rs is C1-C4 alkoxy. In some embodiments of any Formulae described herein, at least one Rs is C1-C3 alkoxy. In some embodiments of any Formulae described herein, at least one Rs is C1-C2 alkoxy. In some embodiments of any Formulae described herein, at least one Rs is Ci alkoxy. In some embodiments of any Formulae described herein, at least one Rs is C2 alkoxy. In some embodiments of any Formulae described herein, at least one Rs is C3 alkoxy. In some embodiments of any Formulae described herein, at least one Rs is C4 alkoxy.

[0066] As defined generally above, each R9 is independently selected from H, halogen, C1-C4 alkyl, and C3-C4 carbocyclyl. In some embodiments of any Formulae described herein, R9 is H. In some embodiments of any Formulae described herein, R9 is halogen. In some embodiments of any Formulae described herein, R9 is C1-C4 alkyl. In some embodiments of any Formulae described herein, R9 is C1-C3 alkyl. In some embodiments of any Formulae described herein, R9 is C1-C2 alkyl. In some embodiments of any Formulae described herein, R9 is Ci alkyl. [0067] In some embodiments of any Formulae described herein, R9 is C2 alkyl. In some embodiments of any Formulae described herein, R₉ is C₃ alkyl. In some embodiments of any Formulae described herein, R₉ is C₄ alkyl. In some embodiments of any Formulae described herein, R9 is C3-C4 carbocyclyl. In some embodiments of any Formulae described herein, R9 is C3 carbocyclyl. In some embodiments of any Formulae described herein, R9 is C4 carbocyclyl. [0068] As defined generally above, each R₁₀ is independently selected from H, halogen, and C1-C4 alkyl. In some embodiments of any Formulae described herein, R10 is H. In some embodiments of any Formulae described herein, R10 is halogen. In some embodiments of any Formulae described herein, R₁₀ is C₁-C₄ alkyl. In some embodiments of any Formulae described herein, R10 is C1-C3 alkyl. In some embodiments of any Formulae described herein, R10 is C1-C2 alkyl. In some embodiments of any Formulae described herein, R10 is C1 alkyl. In some embodiments of any Formulae described herein, R₁₀ is C₂ alkyl. In some embodiments of any Formulae described herein, R₁₀ is C₃ alkyl. In some embodiments of any Formulae described herein, R10 is C4 alkyl. [0069] In some embodiments of any Formulae described herein, R5, R6, and R9 together with the intervening and adjacent atoms, form a C₃-C₆ cycloalkyl, 4- to 8-membered heterocyclyl, a heteroaryl, or an aryl, where the cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more R12. In some embodiments of any Formulae described herein, R5, R₆, and R₉ together with the intervening and adjacent atoms, form a C₃-C₆ cycloalkyl. In some embodiments of any Formulae described herein, R5, R6, and R9 together with the intervening and adjacent atoms, form a C3 cycloalkyl. In some embodiments of any Formulae described herein, R₅, R₆, and R₉ together with the intervening and adjacent atoms, form a C₄ cycloalkyl. In some embodiments of any Formulae described herein, R₅, R₆, and R₉ together with the intervening and adjacent atoms, form a C5 cycloalkyl. In some embodiments of any Formulae described herein, R5, R6, and R9 together with the intervening and adjacent atoms, form a C6 cycloalkyl. In some embodiments of any Formulae described herein, R₅, R₆, and R₉ together with the intervening and adjacent atoms, form a 4- to 8-membered heterocyclyl. In some embodiments of any Formulae described herein, R5, R6, and R9 together with the intervening and adjacent atoms, form a 4- membered heterocyclyl. In some embodiments of any Formulae described herein, R₅, R₆, and R₉ together with the intervening and adjacent atoms, form a 5-membered heterocyclyl. In some embodiments of any Formulae described herein, R5, R6, and R9 together with the intervening and adjacent atoms, form a 6-membered heterocyclyl. In some embodiments of any Formulae described herein, R₅, R₆, and R₉ together with the intervening and adjacent atoms, form a 7- membered heterocyclyl. In some embodiments of any Formulae described herein, R₅, R₆, and R₉ together with the intervening and adjacent atoms, form an 8-membered heterocyclyl. In some embodiments of any Formulae described herein, R5, R6, and R9 together with the intervening and adjacent atoms, form a heteroaryl. In some embodiments of any Formulae described herein, R₅, R6, and R9 together with the intervening and adjacent atoms, form an aryl. In some embodiments of any Formulae described herein, R5, R6, and R9 together with the intervening and adjacent atoms, form a C₃-C₆ cycloalkyl, wherein the cycloalkyl, is substituted with one or more R₁₂. In some embodiments of any Formulae described herein, R5, R6, and R9 together with the intervening and adjacent atoms, form a 4- to 8-membered heterocyclyl, wherein the heterocyclyl is substituted with one or more R₁₂. In some embodiments of any Formulae described herein, R₅, R₆, and R₉ together with the intervening and adjacent atoms, form a heteroaryl, wherein the heteroaryl is substituted with one or more R12. In some embodiments of any Formulae described herein, R5, R6, and R9 together with the intervening and adjacent atoms, form an aryl, wherein the aryl is substituted with one or more R₁₂. [0070] As defined generally above, each R11 is independently selected from H, halogen, C1–C6 alkyl, and C1–C6 alkoxy. In some embodiments of any Formulae described herein, R11 is H. In some embodiments of any Formulae described herein, R₁₁ is halogen. In some embodiments of any Formulae described herein, R11 is C1–C6 alkyl. In some embodiments of any Formulae described herein, R11 is C1–C5 alkyl. In some embodiments of any Formulae described herein, R₁₁ is C₁–C₄ alkyl. In some embodiments of any Formulae described herein, R₁₁ is C₁–C₃ alkyl. In some embodiments of any Formulae described herein, R₁₁ is C₁–C₂ alkyl. In some embodiments of any Formulae described herein, R11 is C1 alkyl. In some embodiments of any Formulae described herein, R11 is C2 alkyl. In some embodiments of any Formulae described herein, R₁₁ is C₃ alkyl. In some embodiments of any Formulae described herein, R₁₁ is C₄ alkyl. In some embodiments of any Formulae described herein, R11 is C5 alkyl. In some embodiments of any Formulae described herein, R11 is C6 alkyl. In some embodiments of any Formulae described herein, R₁₁ is C₁–C₆ alkoxy. In some embodiments of any Formulae described herein, R₁₁ is C₁– C5 alkoxy. In some embodiments of any Formulae described herein, R11 is C1–C4 alkoxy. In some embodiments of any Formulae described herein, R11 is C1–C3 alkoxy. In some embodiments of any Formulae described herein, R11 is C1–C2 alkoxy. In some embodiments of any Formulae described herein, R₁₁ is C₁ alkoxy. In some embodiments of any Formulae described herein, R₁₁ is C₂ alkoxy. In some embodiments of any Formulae described herein, R₁₁ is C₃ alkoxy. In some embodiments of any Formulae described herein, R11 is C4 alkoxy. In some embodiments of any Formulae described herein, R11 is C5 alkoxy. In some embodiments of any Formulae described herein, R₁₁ is C₆ alkoxy. [0071] In some embodiments, each R12 is independently selected from H, halogen, -OH, - NH2, -CN, C1–C6 alkyl, C1–C4 alkoxy, C1–C4 haloalkoxy, C1–C4 haloalkyl, and C3–C4 cycloalkyl, 3- to 10-membered heterocyclyl, heteroaryl, and C₆–C₁₀ aryl. In some embodiments of any Formulae described herein, at least one R12 is selected from H, halogen, C1-C4 alkoxy, or C1-C6 alkyl. In some embodiments of any Formulae described herein, R12 is H. In some embodiments of any Formulae described herein, R₁₂ is halogen. In some embodiments of any Formulae described herein, R₁₂ is -OH. In some embodiments of any Formulae described herein, R12 is -NH2. In some embodiments of any Formulae described herein, R12 is -CN. In some embodiments of any Formulae described herein, R12 is C1–C6 alkyl. In some embodiments of any Formulae described herein, R₁₂ is C₁–C₅ alkyl. In some embodiments of any Formulae described herein, R12 is C1–C4 alkyl. In some embodiments of any Formulae described herein, R12 is C1–C3 alkyl. In some embodiments of any Formulae described herein, R12 is C1–C2 alkyl. In some embodiments of any Formulae described herein, R₁₂ is C₁ alkyl. In some embodiments of any Formulae described herein, R12 is C2 alkyl. In some embodiments of any Formulae described herein, R12 is C3 alkyl. In some embodiments of any Formulae described herein, R12 is C4 alkyl. In some embodiments of any Formulae described herein, R₁₂ is C₅ alkyl. In some embodiments of any Formulae described herein, R₁₂ is C₆ alkyl. In some embodiments of any Formulae described herein, R12 is C1–C4 alkoxy. In some embodiments of any Formulae described herein, R12 is C1– C3 alkoxy. In some embodiments of any Formulae described herein, R12 is C1–C2 alkoxy. In some embodiments of any Formulae described herein, R₁₂ is C₁ alkoxy. In some embodiments of any Formulae described herein, R12 is C2 alkoxy. In some embodiments of any Formulae described herein, R12 is C3 alkoxy. In some embodiments of any Formulae described herein, R12 is C4 alkoxy. In some embodiments of any Formulae described herein, R₁₂ is C₁–C₄ haloalkoxy. In some embodiments of any Formulae described herein, R12 is C1 haloalkoxy. In some embodiments of any Formulae described herein, R12 is C2 haloalkoxy. In some embodiments of any Formulae described herein, Rn is C3 haloalkoxy. In some embodiments of any Formulae described herein, R12 is C4 haloalkoxy. In some embodiments of any Formulae described herein, R12 is C1-C4 haloalkyl. In some embodiments of any Formulae described herein, R12 is Ci haloalkyl. In some embodiments of any Formulae described herein, R12 is C2 haloalkyl. In some embodiments of any Formulae described herein, R12 is C3 haloalkyl. In some embodiments of any Formulae described herein, R12 is C4 haloalkyl. In some embodiments of any Formulae described herein, R12 is C3-C4 cycloalkyl. In some embodiments of any Formulae described herein, R12 is C3 cycloalkyl. In some embodiments of any Formulae described herein, R12 is C4 cycloalkyl. In some embodiments of any Formulae described herein, R12 is C5 cycloalkyl. In some embodiments of any Formulae described herein, R12 is Ce cycloalkyl. In some embodiments of any Formulae described herein, R12 is C7 cycloalkyl. In some embodiments of any Formulae described herein, R12 is Cs cycloalkyl. In some embodiments of any Formulae described herein, R12 is C9 cycloalkyl. In some embodiments of any Formulae described herein, R12 is C10 cycloalkyl. In some embodiments of any Formulae described herein, R12 is 3- to 10-membered heterocyclyl. In some embodiments of any Formulae described herein, R12 is 3 -membered heterocyclyl. In some embodiments of any Formulae described herein, R12 is 4-membered heterocyclyl. In some embodiments of any Formulae described herein, R12 is 5-membered heterocyclyl. In some embodiments of any Formulae described herein, R12 is 6-membered heterocyclyl. In some embodiments of any Formulae described herein, R12 is 7-membered heterocyclyl. In some embodiments of any Formulae described herein, R12 is 8-membered heterocyclyl. In some embodiments of any Formulae described herein, R12 is 9-membered heterocyclyl. In some embodiments of any Formulae described herein, R12 is 10-membered heterocyclyl. In some embodiments of any Formulae described herein, R12 is heteroaryl. In some embodiments of any Formulae described herein, R12 is Ce-Cio aryl. In some embodiments of any Formulae described herein, R12 is Ce aryl. In some embodiments of any Formulae described herein, R12 is Cs aryl. In some embodiments of any Formulae described herein, R12 is C9 aryl. In some embodiments of any Formulae described herein, R12 is C10 aryl.

[0072] In some embodiments, L is selected from a covalent bond and -CH2-. In some embodiments of any Formulae described herein, L is a covalent bond. In some embodiments of any Formulae described herein, L is -CH2-. [0073] In some embodiments, m is an integer selected from 1, 2, and 3. In some embodiments of any Formulae described herein, m is 1. In some embodiments of any Formulae described herein, m is 2. In some embodiments of any Formulae described herein, m is 3.

[0074] In some embodiments, p is an integer selected from 2, 3, 4, 5, and 6. In some embodiments of any Formulae described herein, p is 2. In some embodiments of any Formulae described herein, p is 3. In some embodiments of any Formulae described herein, p is 4. In some embodiments of any Formulae described herein, p is 5. In some embodiments of any Formulae described herein, p is and 6.

[0075] In some embodiments, X3 is selected from CH2, NH, O, and S. In some embodiments of any Formulae described herein, X3 is CH2. In some embodiments of any Formulae described herein, X3 is NH. In some embodiments of any Formulae described herein, X3 is O. In some embodiments of any Formulae described herein, X3 is S.

[0076] In some embodiments, A is selected from C3-C8 cycloalkyl, aryl, and heteroaryl.

In some embodiments of any Formulae described herein, A is C3-C8 cycloalkyl. In some embodiments of any Formulae described herein, A is C3 cycloalkyl. In some embodiments of any Formulae described herein, A is C4 cycloalkyl. In some embodiments of any Formulae described herein, A is C5 cycloalkyl. In some embodiments of any Formulae described herein, A is Ce cycloalkyl. In some embodiments of any Formulae described herein, A is C7 cycloalkyl. In some embodiments of any Formulae described herein, A is Cs cycloalkyl. In some embodiments of any Formulae described herein, A is aryl. In some embodiments of any Formulae described herein, A is heteroaryl.

[0077] In some embodiments, r is an integer from 0 to 3. In some embodiments of any Formulae described herein, r is from 1 to 3. In some embodiments of any Formulae described herein, r is from 0 to 2. In some embodiments of any Formulae described herein, r is 0. In some embodiments of any Formulae described herein, r is 1. In some embodiments of any Formulae described herein, r is 2. In some embodiments of any Formulae described herein, r is 3.

[0078] In some embodiments, a compound of Formula I is selected from:

or a pharmaceutically acceptable salt thereof.

[0079] It should be understood that all isomeric forms are included within the present disclosure, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans configuration. All tautomeric forms are also intended to be included.

[0080] Compounds of the present disclosure, and pharmaceutically acceptable salts, hydrates, solvates, stereoisomers and prodrugs thereof may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present disclosure.

[0081] The compounds of the present disclosure may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present disclosure as well as mixtures thereof, including racemic mixtures, form part of the present disclosure. In addition, the present disclosure embraces all geometric and positional isomers. For example, if a compound of the present disclosure incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the present disclosure, each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound. The compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.

[0082] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of the present disclosure may be atropisomers (e.g., substituted biaryls) and are considered as part of this present disclosure. Enantiomers can also be separated by use of a chiral HPLC column.

[0083] It is also possible that the compounds of the present disclosure may exist in different tautomeric forms, and all such forms are embraced within the scope of the present disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the present disclosure.

[0084] All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this present disclosure, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the present disclosure. Also, for example, all ketoenol and imine-enamine forms of the compounds are included in the present disclosure). Individual stereoisomers of the compounds of the present disclosure may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present disclosure can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”, “ester,” “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.

Pharmaceutical Compositions

[0085] In some embodiments, the present disclosure provides a composition comprising a compound provided by this disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of a compound in the compositions of this disclosure is such that it is effective to measurably inhibit PAD4 in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this disclosure is such that it is effective to measurably inhibit PALM, in a biological sample or in a patient. In certain embodiments, a composition provided by this disclosure is formulated for administration to a patient in need of such composition. In some embodiments, a composition provided by this disclosure is formulated for oral administration to a patient.

[0086] Compositions provided by this disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions provided by this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. [0087] For this purpose, any bland fixed oil may be employed including synthetic mono- or di -glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their poly oxy ethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0088] Pharmaceutically acceptable compositions provided by this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0089] Alternatively, pharmaceutically acceptable compositions provided by this disclosure may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0090] Pharmaceutically acceptable compositions provided by this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches may also be used. For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds provided by this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.

[0091] Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0092] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzyl al konium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0093] Pharmaceutically acceptable compositions provided by this disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

[0094] Preferably, pharmaceutically acceptable compositions provided by this disclosure are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions provided by this disclosure are administered without food. In other embodiments, pharmaceutically acceptable compositions provided by this disclosure are administered with food.

[0095] Pharmaceutically acceptable compositions provided by this disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, as required. In certain embodiments, the compounds provided by this disclosure may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. [0096] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0097] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may also be used in the preparation of injectables.

[0098] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0099] In order to prolong the effect of a compound provided by this disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot inj ectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0100] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds provided by this disclosure with suitable nonirritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature, and therefore melt in the rectum or vaginal cavity and release the active compound.

[0101] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0102] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0103] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0104] Dosage forms for topical or transdermal administration of a compound provided by this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0105] Depending on the intended mode of administration, the disclosed compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts. [0106] The amount of compounds of the present disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.

[0107] A compound of the current disclosure can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the disclosure and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. Exemplary of such other therapeutic agents include corticosteroids, rolipram, calphostin, cytokinesuppressive anti-inflammatory drugs (CSALDs), Interleukin- 10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors, such as deoxyspergualin (DSG); non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; antiviral agents such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf); cytotoxic drugs such as azathi prine and cyclophosphamide; TNF-a inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof. A compound of the current disclosure can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.

[0108] Those additional agents may be administered separately from an inventive compound-containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this disclosure in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another. [0109] As used herein, the term “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, a compound of the present disclosure may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a compound of the current disclosure, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0110] The amount of both a provided compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this disclosure should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of a provided compound can be administered.

[OHl] In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this disclosure may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent.

[0112] The amount of additional therapeutic agent present in the compositions of this disclosure will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0113] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease or disorder being treated. The amount of a compound of the present disclosure in the composition will also depend upon the particular compound in the composition. Method of Synthesizing the Compounds

[0114] The compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.

[0115] The compounds of Formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of those skilled in the art will recognize if a stereocenter exists in the compounds of Formula (I). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley - Interscience, 1994).

[0116] The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.

[0117] By way of example, compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Illustrative methods include but are not limited to those methods described below. Compounds of the present invention can be synthesized by following the steps outlined in General Schemes A, B, C, and D, which comprise different sequences of assembling intermediates. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated.

, , , , , g , , , leaving group, LG₂ is fluorine, chlorine, bromine, iodine, halogen or another suitable leaving group, and R₁₃ is H or OH. Methods of Use [0118] Compounds and compositions described herein are generally useful for the inhibition of PAD4. [0119] The activity of a compound utilized in this disclosure as an inhibitor of PAD4, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine the inhibition of PAD4. Detailed conditions for assaying a compound utilized in this disclosure as an inhibitor of PAD4 are set forth in the Examples below. In some embodiments, a provided compound inhibits PAD4 selectively as compared to PAD2. [0120] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0121] Provided compounds are inhibitors of PAD4 and are therefore useful for treating one or more diseases or disorders associated with PAD4 enzyme activity. Thus, in certain embodiments, the present disclosure provides a method for treating a disease or a disorder associated with PAD4 enzyme activity, comprising the step of administering to a patient in need thereof a compound of the present disclosure, or a pharmaceutically acceptable composition thereof.

[0122] In one embodiment, a disease or a disorder associated with PAD4 enzyme activity is a disease, condition, or disorder mediated by inappropriate PAD4 activity. In some embodiments, a disease or a disorder associated with PAD4 enzyme activity is selected from the group consisting of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, and psoriasis. In a further embodiment, the disease or a disorder associated with PAD4 enzyme activity is rheumatoid arthritis. In a further embodiment, the disease or a disorder associated with PAD4 enzyme activity is systemic lupus. In a further embodiment, the disease or a disorder associated with PAD4 enzyme activity is vasculitis. In a further embodiment, the disease or a disorder associated with PAD4 enzyme activity cutaneous lupus erythematosus. In a further embodiment, the disease or a disorder associated with PAD4 enzyme activity is psoriasis.

[0123] In one embodiment there is provided a method of treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis, which method comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0124] In one embodiment there is provided a method of treatment of rheumatoid arthritis, which method comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound, a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof. In one embodiment there is provided a method of treatment of systemic lupus, which method comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound, a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof. In one embodiment there is provided a method of treatment of vasculitis, which method comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound, a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof. In one embodiment there is provided a method of treatment of cutaneous lupus erythematosus, which method comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound, a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof. In one embodiment there is provided a method of treatment of psoriasis, which method comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound, a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, a disease or a disorder associated with PAD4 enzyme activity is selected from the group consisting of acid-induced lung injury, acne (PAPA), acute lymphocytic leukemia, acute respiratory distress syndrome, Addison’s disease, adrenal hyperplasia, adrenocortical insufficiency, ageing, AIDS, alcoholic hepatitis, alcoholic liver disease, allergen induced asthma, allergic bronchopulmonary, aspergillosis, allergic conjunctivitis, alopecia, Alzheimer’s disease, amyloidosis, amyotropic lateral sclerosis, weight loss, angina pectoris, angioedema, anhidrotic ecodermal dysplasia-ID, ankylosing spondylitis, anterior segment, inflammation, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, bee sting-induced inflammation, Bechet’s disease, Bechet’s syndrome, Bells Palsey, berylliosis, Blau syndrome, bone pain, bronchiolitis, burns, bursitis, cancer, cardiac hypertrophy, carpal tunnel syndrome, catabolic disorders, cataracts, cerebral aneurysm, chemical irritant-induced inflammation, chorioretinitis, chronic heart failure, chronic lung disease of prematurity, chronic lymphocytic leukemia, chronic obstructive pulmonary disease, colitis, complex regional pain syndrome, connective tissue disease, corneal ulcer, crohn’s disease, cryopyrin-associated periodic syndromes, cyrptococcosis, cystic fibrosis, deficiency of the interleukin- 1-receptor antagonist (DIRA), dermatitis, dermatitis endotoxemia, dermatomyositis, diffuse intrinsic pontine glioma, endometriosis, endotoxemia, epicondylitis, erythroblastopenia, familial amyloidotic polyneuropathy, familial cold urticarial, familial Mediterranean fever, fetal growth retardation, glaucoma, glomerular disease, glomerular nephritis, gout, gouty arthritis, graft-versus-host disease, gut diseases, head injury, headache, hearing loss, heart disease, hemolytic anemia, Henoch-Scholein purpura, hepatitis, hereditary periodic fever syndrome, herpes zoster and simplex, HIV-1, Hodgkin’s disease, Huntington’s disease, hyaline membrane disease, hyperammonemia, hypercalcemia, hypercholesterolemia, hyperimmunoglobulinemia D with recurrent fever (HIDS), hypoplastic and other anemias, hypoplastic anemia, idiopathic thrombocytopenic purpura, incontinentia pigmenti, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, insect bite-induced inflammation, iritis, irritant-induced inflammation, ischemia/reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, kidney injury caused by parasitic infections, kidney injury caused by parasitic infections, kidney transplant rejection prophylaxis, leptospiriosis, leukemia, Loeffler’s syndrome, lung injury, lupus, lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticaria deafness amyloidosis), multiple sclerosis, muscle wasting, muscular dystrophy, myasthenia gravis, myocarditis, mycosis fungoides, myelodysplastic syndrome, myositis, nasal sinusitis, necrotizing enterocolitis, neonatal onset multisystem inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathological diseases, non-allergen induced asthma, obesity, ocular allergy, optic neuritis, organ transplant, osteoarthritis, otitis media, Paget’s disease, pain, pancreatitis, Parkinson’s disease, pemphigus, pericarditis, periodic fever, periodontitis, peritoneal endometriosis, pertussis, pharyngitis and adenitis (PFAPA syndrome), plant irritant-induced inflammation, pneumonia, pneumonitis, pneumosysts infection, poison ivy/ urushiol oil-induced inflammation, polyarteritis nodosa, polychondritis, polycystic kidney disease, polymyositis, psoriasis, psychosocial stress diseases, pulmonary disease, pulmonary hypertension, pulmonary fibrosis, pyoderma gangrenosum, pyogenic sterile arthritis, renal disease, retinal disease, rheumatic carditis, rheumatic disease, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cell, sickle cell anemia, silica-induced disease, Sjogren’s syndrome, skin diseases, sleep apnea, solid tumors, spinal cord injury, Stevens- Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, temporal arteritis, tenosynovitis, thrombocytopenia, thyroiditis, tissue transplant, TNF receptor associated periodic syndrome (TRAPS), toxoplasmosis, transplant, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticarial, uveitis, Wegener’s granulomatosis, interstitial lung disease, psoriatic arthritisjuvenile idiopathic arthritis, Sjogren’s syndrome, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, antiphospholipid antibody syndrome, sepsis, deep vein thrombosis, fibrosis, Alzheimer’s, scleroderma and CREST syndrome.

[0126] In one embodiment, the disclosure provides a compound, or a pharmaceutically acceptable salt thereof, for use in therapy. In another embodiment, the disclosure provides a compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or a disorder mediated by inappropriate PAD4 activity. In another embodiment, the disclosure provides a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, for use in the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis. In another embodiment, the disclosure provides a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, for use in the treatment of rheumatoid arthritis. In another embodiment, the disclosure provides a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, for use in the treatment of systemic lupus. In another embodiment, the disclosure provides a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, for use in the treatment of vasculitis. In another embodiment, the disclosure provides a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, for use in the treatment of cutaneous lupus erythematosus. In another embodiment, the disclosure provides a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, for use in the treatment of psoriasis. In another embodiment, the disclosure provides the use of a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a disorder mediated by inappropriate PAD4 activity. In another embodiment, the disclosure provides the use of a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis. In another embodiment, the disclosure provides the use of a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of rheumatoid arthritis. In another embodiment, the disclosure provides the use of a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of systemic lupus. In another embodiment, the disclosure provides the use of a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of vasculitis. In another embodiment, the in disclosure vention provides the use of a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cutaneous lupus erythematosus. In another embodiment, the disclosure provides the use of a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of psoriasis. In a further embodiment, the disclosure provides a pharmaceutical composition for the treatment or prophylaxis of a disease or a disorder mediated by inappropriate PAD4 activity comprising a provided compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof. In a further embodiment, the disclosure provides a pharmaceutical composition for the treatment or prophylaxis of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis, comprising a provided compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof. In a further embodiment, the disclosure provides a pharmaceutical composition for the treatment or prophylaxis of rheumatoid arthritis comprising a provided compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof. In a further embodiment, the disclosure provides a pharmaceutical composition for the treatment or prophylaxis of systemic lupus comprising a provided compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof. In a further embodiment, the disclosure provides a pharmaceutical composition for the treatment or prophylaxis of vasculitis comprising a provided compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof. In a further embodiment, the disclosure provides a pharmaceutical composition for the treatment or prophylaxis of cutaneous lupus erythematosus comprising a provided compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof. In a further embodiment, the disclosure provides a pharmaceutical composition for the treatment or prophylaxis of psoriasis comprising a provided compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.

EXAMPLES

[0127] The following Examples have been prepared, isolated and characterized using the methods disclosed herein. The following examples demonstrate a partial scope of the disclosure and are not meant to be limiting of the scope of the disclosure.

Abbreviations

AcOH acetic acid

ACN or MeCN acetonitrile

BAEE N-benzoyl-L-arginine ethyl ester

BH₃ borane

Boc zez7-butyl oxycarbonyl

BOC2O di-tert-butyl dicarbonate

Bn benzyl

Bu butyl z-Bu isobutyl

Z-Bu ze/7-butyl

Z-BuOH zez7-butanol

BSA bovine serum albumin

CD3OD, Methanol-d4 deuteromethanol

CHAPS 3-[(3-cholamidopropyl)dimethylammonio]-l- propanesulfonate

CS2CO3 cesium carbonate

D₂O deuterium oxide

DCM dichloromethane

DEA diethanolamine

DIPEA diisopropylethylamine

DMF dimethyl formamide

DMSO dimethyl sulfoxide

DMS04 deutero-dimethyl sulfoxide DTT dithiothreitol equiv, eq. equivalent(s) Et ethyl Et₃N triethylamine ESI electrospray ionization EtOAc ethyl acetate H2SO4 sulfuric acid HATE l-[Bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

HC1 hydrochloric acid HEPES 4-(2-hy droxy ethyl)- 1 -piperazineethanesulfonic acid HPLC high-performance liquid chromatography Prep-HPLC preparative high-performance liquid chromatography K2CO3 potassium carbonate KNO3 potassium nitrate LCMS liquid chromatography mass spectrometry LiAlH₄ lithium aluminium hydride Me methyl MeOH methanol Mel methyl iodide MgSO₄ magnesium sulfate min, min. minute(s) MS Mass spectrometry MsCl methanesulfonyl chloride NaCl sodium chloride Na₂CO₃ sodium carbonate NaH sodium hydride NaHCO₃ sodium bicarbonate NaIO₄ sodium periodate NaOH sodium hydroxide Na₂SO₄ sodium sulfate Na₂S₂O₄ Sodium dithionite NBS N-bromosuccinimide NH₃ ammonia NH₄C1 ammonium chloride

NMR Nuclear magnetic resonance

Pd(dppf)C12 [1,1 '-Bi s(diphenylphosphino)ferrocene]/W/«6//z/«7(II) di chloride

Pd2(dba)3 T ri s(bibenzyli deneacetone)dipalladium(O)

PEPPSi-IPr [l,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3- chloropy ri dy 1 )pal 1 adium(II) di chi ori de

Ph phenyl

Pr propyl z-Pr isopropyl

IPA isopropanol rt room temperature

RT retention time

RuCh Ruthenium(III)chloride

SEM 2-(Trimethylsilyl)ethoxymethyl

SFC supercritical fluid chromatography

Si-Pyridine functionalized silica gel: Silicycle R43030B, 40-63 micron particle size

SOCI2 thionyl chloride

TBAF tetrabutylammonium fluoride

TBDPS tertbutyldiphenylsilyl

TBS tertbutyldimethylsilyl

TFA trifluoroacetic acid

THF tetrahydrofuran

Ti(OiPr)₄ titanium isopropoxide

TLC thin layer chromatography

Prep-TLC preparative thin layer chromatography

TPEN N,NN',;V'-tetrakis(2-pyridinylmethyl)-l ,2- ethanediamine

Ts 4-toluenesulfonyl

TsCl 4-toluenesulfonyl chloride

Analytical Procedures and Methods

Description of Preparatory HPLC and analytical LCMS methods: [0128] Method A: Column: XBridge Prep Shield RP Cl 8, 30*150 mm, 5 pm; Mobile Phase A: 0.05% TFA in water, Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 24% B to 37% B in 8 min; Wavelength: 254 nm/220 nm.

[0129] Method B: Column: HALO 90A Cl 8, 3.0*30 mm, 2.0 pm; Mobile Phase A: 0.05% TFA in water, Mobile Phase B: ACN + 0.05%TFA; Flow rate: 1.5 mL/min; [Gradient]; Wavelength: 254 nm.

Method B Variations:

[0130] Method C: Column: SunFire C18 OBD Prep, 19*250 mm, 5 pm; Mobile Phase A: 0.05% TFA in water, Mobile Phase B: ACN; Flow rate: 25 mL/min; 32% B to 36% B in 6.5 min, 36% B; Wavelength: 254/210 nm.

[0131] Method D: Column: Shim-pack Scepter Cl 8, 3.0*33 mm, 3.0 pm; Mobile Phase A: 5 mM NH4HCO3 in water, Mobile Phase B: ACN; Flow rate: 1.5 mL/min; [Gradient];

Wavelength: 254 nm.

Method D Variations:

[0132] Method E: Column: Xselect CSH Prep Cl 8, 30*150 mm, 5 pm; Mobile Phase A: 0.05% TFA in water, Mobile Phase B: ACN; [Flow Rate]; [Gradient]; Wavelength: 254 nm/220 nm.

Method E Variations:

[0133] Method F: Column: XBridge Prep OBD Cl 8, 30*150 mm, 5 pm; Mobile Phase A:

10 mM NH4HCO3 in water, Mobile Phase B: ACN; Flow rate: 60 mL/min; 22% B to 52% B in

10 min; Wavelength: 254 nm/220 nm

[0134] Method G: Column: XBridge Prep Phenyl OBD Cl 8, 19*250 mm, 5 pm; Mobile Phase A: 0.05% TFA in water, Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 22% B to 52% B in 10 min; Wavelength: 254 nm/220 nm.

[0135] Method H: Column: HALO C18, 4.6*100 mm, 2.7 pm; Mobile Phase A: 0.05% TFA in water, Mobile Phase B: ACN + 0.05% TFA; Flow rate: 1.5 mL/min; Gradient: 10% B to 95% B in 6 min, hold at 95% for 2 min, 95% B to 5% B in 2 min; Wavelength: 254 nm.

[0136] Method I: Column: XBridge Cl 8, 19*200 mm, 5 pm; Mobile Phase A: 0.05% TFA in water / ACN 95:5, Mobile Phase B: 0.05% TFA in water / ACN 5:95; Flow rate: 20 mL/min; [Gradient]; Wavelength: 220 nm.

Method I Variations:

[0137] Method J: Column: XBridge C18, 2.1*50, 1.7 pm, Mobile Phase A: 0.05% TFA in water / ACN 95:5, Mobile Phase B: 0.05% TFA in water / ACN 5:95; Flow rate: l.O mL/min;

Gradient: 0% B to 100% B in 3 min, hold at 100% B for 0.5 min; Wavelength: 220 nm. [0138] Method K: Column: HALO C18, 3.0*30 mm, 3.0 pm; Mobile Phase A: 0.05% TFA in water, Mobile Phase B: 0.05% TFA in ACN; Flow rate: 1.5 mL/min; [Gradient];

Wavelength: 254 nm.

Method K Variations:

Synthetic Examples

[0139] The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Illustrative methods include but are not limited to those methods described below. Compounds of the present invention can be synthesized by following the steps outlined in General Schemes A, B, C, and D, which comprise different sequences of assembling intermediates. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated.

Example 1. (R)-2,5,5-trimethyl-l²-(3-methyl-7-(((S)-morpholin-3-yl)methyl)-8-oxo-5,6,7,8- tetrahydro-3H-imidazo[4,5-b][l,6]naphthyridin-2-yl)-l¹H-3-aza-l(6,l)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one

Synthesis of Intermediate II:

Synthesis of Intermediate 1A

[0140] To a solution of methyl 6-chloro-lH-pyrrolo[2,3-b]pyridine-2-carboxylate (10.0 g, 47.5 mmol) in DMF (500 mL) at 0 °C under nitrogen was added NaH (60% w/w, 5.6 g, 233 mmol) in portions, and the resulting mixture was stirred at rt for 0.5 h. The reaction mixture was cooled to 0 °C, and (2-(chloromethoxy)ethyl)trimethylsilane (16.0 g, 96.0 mmol) was added dropwise. The resulting mixture was stirred at rt for 5 h, then diluted with water (2 L) and extracted with ethyl acetate (2 L). The combined organic extract was washed with water (2*2 L) and brine (2*2 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 5: 1) to afford Intermediate 1A (12 g) as a white oil. LCMS (ESI, m/z): 341 [M+H]⁺ .

Synthesis of Intermediate IB

[0141] To a solution of Intermediate 1A (12 g, 35.2 mmol) in 1,4-dioxane (400 mL) were added tributyl(l -ethoxy vinyl)stannane (20 g, 55 mmol), DavePhos (3.0 g, 7.6 mmol), and Pd(dppf)Ch (3.0 g, 3.7 mmol) under nitrogen, and the resulting mixture was stirred at 90 °C overnight in a sealed vessel. The reaction mixture was acidified with aqueous HC1 (I M, 100 mL), stirred at rt for 0.5 h, then diluted with water (1 L) and extracted with ethyl acetate (2*1 L). The combined organic extract was washed with water (2*2 L) and brine (2 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 4: 1) to afford Intermediate IB (10 g) as a yellow solid. LCMS (ESI, m/z): 349 [M+H]⁺ .

Synthesis of Intermediate 1C

[0142] To a solution of Intermediate IB (10.0 g, 28.7 mmol) in THF (200 mL) were added (S)-2-methylpropane-2-sulfinamide (14 g, 115 mmol) and Ti(OiPr)4 (65 g, 230 mmol) under nitrogen, and the resulting mixture was stirred at 60 °C overnight. The reaction mixture was poured into saturated aqueous NELCl (1 L). The solids were filtered out and the filtrate was diluted with water (1 L) and extracted with ethyl acetate (2*2 L). The combined organic extract was washed with water (3 L) and brine (3 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 2: 1) to afford Intermediate 1C (8 g) as a yellow solid. LCMS (ESI, m/z): 480 [M+H]⁺ .

Synthesis of Intermediate ID

[0143] To a solution of Intermediate 1C (8.0 g, 16.7 mmol) in THF (200 mL) at -78 °C under nitrogen was added L-sel ectride (2 M in THF, 20 mL) in portions, and the resulting mixture was stirred at -78 °C for 6 h. The reaction was then quenched with saturated aqueous NH4CI (500 mL) at 0 °C, and extracted with ethyl acetate (2*500 mL). The combined organic extract was washed with brine (1000 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 1 : 1) to afford Intermediate ID (7 g) as yellow solid. LCMS (ESI, m/z): 482 [M+H]⁺ .

Synthesis of Intermediate IE

[0144] A solution of Intermediate ID (6.0 g, 12.5 mmol) in HC1 (4 M in EtOAc, 150 mL) was stirred at rt for 3 h, then concentrated under vacuum. The crude product was diluted with saturated aqueous NaHCCh (1 L), then THF (200 mL) and BOC2O (3.5 g, 16.0 mmol) were added. The resulting mixture was stirred at rt for 2 h, then extracted with ethyl acetate (2*1 L), washed with water (2 L) and brine (2 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 3: 1). The resultant mass was repurified by flash column chromatography on C18 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 30% B to 100% B). The pure fractions were concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to afford Intermediate IE (3.5 g) as a white solid. LCMS (ESI, m/z): 348 [M+H]⁺ .

Synthesis of Intermediate IF

[0145] To a solution of tert-butyl 8-bromo-2,2-dimethyloctanoate (1.5 g, 4.9 mmol, WO2021222353) in DMF (50 mL) were added CS2CO3 (4.8 g, 14.6 mmol) and Intermediate IE (1.7 g, 4.9 mmol) under nitrogen, and the resulting mixture was stirred at 65 °C for 1 h. The reaction was then diluted with water (200 mL) and extracted with ethyl acetate (2*200 mL). The combined organic extract was washed with water (2*400 mL) and brine (2*400 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 5: 1) to afford Intermediate IF (1.8 g) as a yellow solid. LCMS (ESI, m/z): 574 [M+H]⁺ .

Synthesis of Intermediate 1G

[0146] To a solution of Intermediate IF (1.8 g, 3.1 mmol) in DCM (30 mL) was added TFA (6 mL). The resulting mixture was stirred at rt for 3 h, then concentrated under vacuum to afford crude Intermediate 1G (1.2 g) as a yellow oil. LCMS (ESI, m/z): 418 [M+H]⁺ .

Synthesis of Intermediate 1H

[0147] To a solution of Intermediate 1G (1.6 g, 3.8 mmol) and HATU (1.8 g, 4.6 mmol) in DMF (30 mL) at rt under nitrogen was added DIPEA (1.5 mL, 19.2 mmol). The resulting mixture was stirred at rt for 1 h, then diluted with water (150 mL) and extracted with ethyl acetate (2*150 mL). The combined organic extract was washed with water (2*300 mL) and brine (2*300 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate =3: 1) to afford Intermediate 1H (700 mg) as a white solid. LCMS (ESI, m/z): 400 [M+H]⁺ .

Synthesis of Intermediate II

[0148] To a solution of Intermediate 1H (400 mg, 1 mmol) in methanol (10 mL) and water (5 mL) at rt was added NaOH (200 mg, 5 mmol), and the resulting mixture was stirred at 50 °C for 2 h. The reaction mixture was acidified to pH 2 with aqueous HC1 (1 M), stirred for at rt for 0.5 h, then extracted with ethyl acetate (2*30 mL). The combined organic extract was washed with brine (2*60 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford Intermediate II (350 mg) as a white solid. LCMS (ESI, m/z): 358 [M+H]⁺ . Synthesis of Intermediate 1 J

[0149] To a solution of tert-butyl 2-chl oro-7, 8-dihydro-5H-l, 6-naphthyri dine-6- carboxylate (20.0 g, 74.4 mmol) in ethyl acetate (500 mL) at 0 °C under nitrogen was added a solution of NaIO₄ (47.8 g, 223 mmol) in water (250 mL), and the resulting mixture was stirred at 0 °C for 10 min, followed by portionwise addition of RuCh (2.31 g, 11.2 mmol). The resulting mixture was stirred at 15 °C overnight, then diluted with saturated aqueous Na2SCL (1 L) and extracted with ethyl acetate (2*1 L). The combined organic extract was washed with brine (2.5 L), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 4: 1) to afford Intermediate 1 J (20 g) as a brown solid. LCMS (ESI, m/z): 283 [M+H]⁺ .

Synthesis of Intermediate IK

[0150] To a solution of Intermediate 1J (1 g, 3.54 mmol) in DCM (30 mL) was added TFA (6 mL). The resulting mixture was stirred at rt for 1 h, then concentrated under vacuum to afford crude Intermediate IK (1.2 g). LCMS (ESI, m/z): 183 [M+H]⁺ .

Synthesis of Intermediate IL

[0151] To a solution of crude Intermediate IK (1.2 g) in THF (60 mL) at 0 °C under nitrogen was added NaH (60% w/w, 789 mg, 32.9 mmol) in portions, and the resulting mixture was stirred at rt for 0.5 h. The reaction mixture was cooled to 0 °C, and (R)-tetrahydro-3H- [l,2,3]oxathiazolo[4,3-c][l,4]oxazine 1,1-dioxide (1.77 g, 9.86 mmol, J. Med. Chem. 2019, 62, 18, 8609) was added. The resulting mixture was stirred at rt for 2 h, then diluted with water (300 mL) and extracted with ethyl acetate (2*300 mL). The combined organic extract was washed with brine (600 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on C18 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 0% B to 50% B) to afford Intermediate 1L (3 g) as a yellow oil. LCMS (ESI, m/z): 382 [M+H]⁺ . Synthesis of Intermediate 1M [0152] A solution of Intermediate 1L (2.5 g, 6.91 mmol) in methanol (15 mL) and HCl (2 M in EtOAc, 15 mL) was stirred at 50 °C for 2 h in a sealed vessel. The solids were filtered out and the filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography on C18 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 0% B to 50% B) to afford Intermediate 1M (830 mg) as a yellow solid. LCMS (ESI, m/z): 282 [M+H]⁺ . Synthesis of Intermediate 1N [0153] A mixture of Intermediate 1M (600 mg, 2.13 mmol), NaHCO3 (1.08 g, 10.6 mmol) and Boc2O (930 mg, 4.26 mmol) in THF (20 mL) and water (20 mL) was stirred at rt overnight. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (2*100 mL). The combined organic extract was washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate =1:1) to afford Intermediate 1N (620 mg) as a white solid. LCMS (ESI, m/z): 382 [M+H]⁺ . Synthesis of Intermediate 1O [0154] To a solution of Intermediate 1N (620 mg, 1.62 mmol) in glycol (8 mL, 1.62 mmol) and t-BuOH (8 mL, 1.62 mmol) was added N-methyl-1-phenyl-methanamine (1.97 g, 16.2 mmol), and the resulting mixture was stirred at 50 °C for 2 days. The solids were filtered and the filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 5:1) to afford Intermediate 1O (400 mg) as a white solid. LCMS (ESI, m/z): 467 [M+H]⁺ . Synthesis of Intermediate 1P [0155] To a solution of Intermediate 1O (400 mg, 0.86 mmol) in H₂SO₄ (5. mL, 93.9 mmol) at 0 °C was added KNO3 (260 mg, 2.57 mmol) portionwise, and the resulting mixture was stirred at 20 °C for 3 h. The reaction mixture was poured into ice-water (100 mL) and washed with ethyl acetate (2*100 mL). The remaining aqueous phase was advanced into the next step directly without further processing. LCMS (ESI, m/z): 322 [M+H]⁺ .

Synthesis of Intermediate IQ

[0156] To the aqueous solution from the previous step was added NaHCCh (1.45 g, 14.3 mmol), BOC2O (392 mg, 1.79 mmol), and THF (50 mL). The resulting mixture was stirred at rt overnight, then diluted with water (50 mL) and extracted with ethyl acetate (2*150 mL). The combined organic extract was washed with water (300 mL) and brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate =2:3) to afford Intermediate IQ (260 mg). LCMS (ESI, m/z): 422 [M+H]⁺ .

Synthesis of Intermediate 1R

[0157] To a solution of Intermediate IQ (260 mg, 0.62 mmol) in methanol (3 mL) was added dropwise a solution of NH4CI (330 mg, 6.17 mmol) in water (3 mL), followed by portionwise addition of zinc powder (403 mg, 6.17 mmol), and the resulting mixture was stirred at rt for 3 h. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was diluted with water (50 mL) and ethyl acetate (2*50 mL). The combined organic extract was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (100% ethyl acetate) to afford Intermediate 1R (200 mg) as a yellow solid. LCMS (ESI, m/z): 392 [M+H]⁺ .

Synthesis of Intermediate IS

[0158] To a solution of Intermediate II (100 mg, 0.3 mmol) and DIPEA (109 mg, 0.8 mmol) in DMF (3 mL) at rt under nitrogen was added HATU (128 mg, 0.3 mmol). The resulting mixture was stirred at rt for 10 min, then added dropwise into a solution of Intermediate 1R (110 mg, 0.3 mmol) in DMF (1 mL) at rt. The resulting mixture was stirred at 40 °C overnight, then diluted with water (20 mL) and extracted with ethyl acetate (2*20 mL). The combined organic extract was washed with water (2*40 mL) and brine (2*40 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by Prep-TLC (petroleum ether / ethyl acetate =3 : 1) to afford Intermediate 1 S (150 mg) as a yellow solid. LCMS (ESI, m/z): 731 [M+H]⁺ . Synthesis of Intermediate 1T [0159] A solution of Intermediate 1S (130 mg, 0.2 mmol) in acetic acid (3 mL) was stirred at 100 °C overnight. The resulting solution was concentrated under vacuum to afford Intermediate 1T (120 mg) as a yellow oil which was advanced into the next step directly without further processing. LCMS (ESI, m/z): 713 [M+H]⁺ . Synthesis of Example 1 [0160] To a solution of Intermediate 1T (120 mg, 0.17 mmol) in DCM (4 mL) was added TFA (1 mL). The resulting mixture was stirred at rt for 1 h, then concentrated under vacuum. The crude product was purified by Prep-HPLC (Method A, RT: 7.8 min). The pure fractions were concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to afford Example 1 (43.6 mg) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 9.03 (s, br, 1H), 8.92 (s, br, 1H), 8.52 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.26 (s, 1H), 7.21 (d, J = 8.0 Hz, 1H), 5.17 - 5.12 (m, 1H), 4.96 - 4.85 (m, 1H), 4.68 - 4.64 (m, 1H), 4.02 (s, 3H), 4.01- 3.89 (m, 3H), 3.81 - 3.66 (m, 4H), 3.60 - 3.48 (m, 2H), 3.37 - 3.31 (m, 3H), 3.11 - 3.07 (m, 1H), 1.98 - 1.89 (m 1H), 1.68 - 1.66 (m, 2H), 1.45 - 1.33 (m, 8H), 1.21 (s, 3H), 1.11-1.08 (m, 2H), 0.95 (s, 3H). LCMS (ESI, m/z): 613 [M+H]⁺. LCMS RT: 0.69 min (Method B1).

Example 2. (R)-2,5,5-trimethyl-1²-(1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one

Synthesis of Intermediate 2A [0161] To a solution of 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one (5.0 g, 30.2 mmol) in THF (300 mL) at 0 °C under nitrogen was added NaH (60% w/w, 0.90 g, 36.3 mmol) in portions, and the resulting mixture was stirred at rt for 0.5 h. The reaction was cooled to 0 °C, and (R)- tetrahydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1,1-dioxide (6.51 g, 36.3 mmol) was added. The resulting mixture was stirred at rt for 2 h, then cooled to 0 °C, quenched with water (5 mL), and concentrated under vacuum. The crude product was purified by flash column chromatography on Cl 8 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 0% B to 100% B) to afford Intermediate 2A (9 g) as a yellow solid. LCMS (ESI, m/z): 345 [M+H]⁺ .

Synthesis of Intermediate 2B

[0162] To a solution of Intermediate 2A (9.0 g, 26.1 mmol) in methanol (200 mL) was added aqueous HC1 (2 M, 30 mL). The resulting mixture was stirred at rt for 2 h, then concentrated under vacuum. The crude product was purified by flash column chromatography on Cl 8 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 0% B to 100% B) to afford Intermediate 2B (6 g) as a yellow solid. LCMS (ESI, m/z): 256 [M+H]⁺.

Synthesis of Intermediate 2C

[0163] To a solution of Intermediate 2B (6.0 g, 22.7 mmol) in H2SO4 (60 mL) at 0 °C was added KNO3 (6.9 g, 68.1 mmol) portionwise, and the resulting mixture was stirred at rt for 3 h. The reaction was poured into ice-water (500 mL) and washed with ethyl acetate (2*500 mL). The remaining aqueous phase was advanced into the next step directly without further processing. LCMS (ESI, m/z): 310 [M+H]⁺.

Synthesis of Intermediate 2D

[0164] To the aqueous solution from the previous step was added Na2CC>3 (19.6 g, 185 mmol), THF (100 mL), and BOC2O (4.2 g, 19.4 mmol). The resulting mixture was stirred at rt overnight, then extracted with ethyl acetate (2*500 mL). The combined organic extract was washed with water (I L) and brine (1 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 2:3) to afford Intermediate 2D (2 g) as a yellow solid. LCMS (ESI, m/z): 410 [M+H]⁺ .

Synthesis of Intermediate 2E

[0165] To a solution of Intermediate 2D (2.0 g, 4.89 mmol) and methylamine hydrochloride (0.7 g, 9.77 mmol) in MeCN (50 mL) at rt was added DIPEA (1.9 g, 14.7 mmol), and the resulting mixture was stirred at rt for 2 h. The solids were filtered out and the filtrate was concentrated under vacuum. The resulting crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 1 :5) to afford Intermediate 2E (1 g) as a yellow solid. LCMS (ESI, m/z): 421 [M+H]⁺ .

Synthesis of Intermediate 2F

[0166] To a solution of Intermediate 2E (1.0 g, 2.38 mmol) in methanol (24 mL) was added a solution of NH4CI (1.27 g, 23.8 mmol) in water (6 mL), followed by portionwise addition of zinc powder (1.55 g, 23.8 mmol), and the resulting mixture was stirred at rt for 3 h. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was diluted with water (100 mL) and extracted with ethyl acetate (2*100 mL). The combined organic extract was washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (100% ethyl acetate) to afford Intermediate 2F (700 mg) as a yellow solid. LCMS (ESI, m/z): 391 [M+H]⁺ .

Synthesis of Intermediate 2G

[0167] To a solution of Intermediate II (80 mg, 0.22 mmol) in DMF (4 mL) at rt under nitrogen were added HATU (128 mg, 0.34 mmol) and DIPEA (0.05 mL, 0.67 mmol), and the resulting mixture was stirred at rt for 10 min, followed by addition of Intermediate 2F (105 mg, 0.27 mmol). The resulting mixture was stirred at rt overnight, then directly purified by flash column chromatography on C18 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 0% B to 100% B) to afford Intermediate 2G (140 mg) as a yellow solid. LCMS (ESI, m/z): 730 [M+H]⁺ .

Synthesis of Intermediate 2H

[0168] A solution of Intermediate 2G (180 mg, 0.24 mmol) in AcOH (10 mL, 174 mmol) was stirred at 70 °C for 3 h. The mixture was concentrated under vacuum to afford crude Intermediate 2H (150 mg) as a yellow solid. LCMS (ESI, m/z): 712 [M+H]⁺ .

Synthesis of Example 2

[0169] To a solution of Intermediate 2H (150 mg, 0.21 mmol) in DCM (3 mL) was added TFA (1 mL). The resulting mixture was stirred at rt for 1 h, then concentrated under vacuum. The crude product was purified by Prep-HPLC (Method C, RT: 5.17 min). The pure fractions were concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to afford Example 2 (117 mg) as a white solid. ^!H NMR (400 MHz, DMSO-deMhO) 8 8.27 (s, 1H), 8.06 (d, J= 8.0 Hz, 1H), 7.61 (s, 1H), 7.20 (d, J= 8.0 Hz, 1H), 7.13 (s, 1H), 5.25 - 5.05 (m, 1H), 4.85 - 4.87 (m, 1H), 4.54 - 4.50 (m, 1H), 4.03 - 3.90 (m, 6H), 3.75 - 3.69 (m, 2H), 3.64 - 3.52 (m, 3H), 3.32 - 3.19 (m, 4H), 3.11 - 3.01 (m, 1H), 1.97 - 1.87 (m, 1H), 1.75 - 1.51 (m, 2H), 1.50 - 1.26 (m, 8H), 1.21 (s, 3H), 1.15 - 0.98 (m, 2H), 0.95 (s, 3H). LCMS (ESI, m/z): 612 [M+H]⁺. LCMS RT: 1.247 min (Method B2).

Example 3. (R)-l²-(7-((S)-2-amino-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H- imidazo[4,5-b][l,6]naphthyridin-2-yl)-2,5,5-trimethyl-l¹H-3-aza-l(6,l)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one

Synthesis of Example 3 from intermediate 1J:

Synthesis of 3G from methyl (2S)-2-(tert-butoxycarbonylamino)-3-hydroxy-propanoate :

Synthesis of Intermediate 3A

[0170] To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-hydroxy-propanoate (90 g, 410 mmol) and imidazole (30.7 g, 452 mmol) in DCM (900 mL) at 0 °C was added TBSC1 (80.4 g, 534 mmol). The resulting mixture was stirred at 20 °C for 2 h, then diluted with water (1 L) at 0 °C and extracted with DCM (3*800 mL). The combined organic extract was washed with brine (2*1 L), dried over anhydrous Na₂SO₄, filtered, and concentrated to afford crude Intermediate 3A (140 g) as a light yellow oil.¹H NMR (400 MHz, CDCl₃) δ: 5.34 (d, J = 8.4 Hz, 1H), 4.36 (d, J = 8.8 Hz, 1H), 4.06 (d, J = 2.4 Hz, 1H), 4.03 (d, J = 2.4 Hz, 1H), 3.75 (s, 3H), 1.46 (s, 9H), 0.87 (s, 9H), 0.03 (d, J = 5.2 Hz, 6H). Synthesis of Intermediate 3B [0171] To a suspension of LiAlH4 (27.9 g, 734 mmol) in THF (1.2 L) at 0°C was added a solution of Intermediate 3A (144 g, 432 mmol) in THF (300 mL), and the resulting mixture was stirred at 0 °C for 1 h. The reaction was then quenched with saturated aqueous NH₄Cl (800 mL), the solids were filtered out, and the filtrate was extracted with ethyl acetate (2*800 mL). The combined organic extract was washed with brine (800 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford crude Intermediate 3B (110 g) as light yellow oil.¹H NMR (400 MHz, CDCl₃) δ: 5.06 (s, 1H), 3.75 - 3.58 (m, 4H), 2.70 - 2.61 (m, 1H), 1.38 (s, 9H), 0.82 (s, 9H), 0.00 (s, 6H). Synthesis of Intermediate 3C [0172] To a solution of imidazole (147 g, 2.16 mol) in DCM (700 mL) at 0 °C was added a solution of SOCl2 (77.1 g, 648 mmol) in DCM (400 mL), and the resulting mixture was stirred at 18 °C for 1 h. The reaction was cooled to -10 °C, and a solution of Intermediate 3B (110 g, 360 mmol) in DCM (600 mL) was added. The resulting mixture was stirred at 18 °C for 1 h, then diluted with aqueous citric acid (10%, 800 mL) and extracted with DCM (2*1 L). The combined organic extract was washed with water (2*1 L), dried over anhydrous Na2SO4, filtered, and concentrated to afford crude Intermediate 3C (104g) as light yellow oil.¹H NMR (400 MHz, CDCl₃) δ: 5.00 - 4.98 (m, 1H), 4.83 - 4.72 (m, 2H), 4.07 - 4.03 (m, 1H), 3.79 - 3.72 (m, 1H), 1.53 (s, 9H), 0.89 (s, 9H), 0.07 (s, 6H). Synthesis of Intermediate 3D [0173] Two batches were conducted in parallel. To a solution of Intermediate 3C (52 g, 148 mmol) in MeCN (1000 mL) at 18 °C was added RuCl3 (30.7 mg, 148 µmol) and a solution of NaIO4 (31.6 g, 148 mmol) in H2O (500 mL). The resulting mixture was stirred at 18 °C for 1 h, then the two batches were combined, diluted with water (1 L), and extracted with DCM (2*1 L). The combined organic extract was washed with water (2*500 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford crude Intermediate 3D (80 g) as a light yellow solid.¹H NMR (400 MHz, CDCl3) δ: 4.64 - 4.58 (m, 2H), 4.28 - 4.27 (m, 1H), 3.89 - 3.76 (m, 2H), 1.56 (s, 9H), 0.90 (s, 9H), 0.09 (s, 6H). Synthesis of Intermediate 3E [0174] To a solution of Intermediate 3D (85 g, 231 mmol) in THF (850 mL) was added TBAF (1 M, 277 mL). The resulting mixture was stirred at 20 °C for 1 h, then diluted with saturated aqueous NH₄Cl (100 ml) and extracted with ethyl acetate (2*800 mL). The combined organic extract was washed with water (2*500 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 2:1) to afford Intermediate 3E (20 g) as light yellow oil.¹H NMR (400 MHz, CDCl3) δ: 5.05 (d, J = 7.6 Hz, 2H), 4.57 - 4.44 (m, 2H), 3.81 - 3.73 (m, 3H), 1.45 (s, 9H). Synthesis of Intermediate 3F [0175] To a solution of imidazole (42.3 g, 621 mmol) in DCM (200 mL) at 0 °C was added a solution of SOCl₂ (22.2 g, 186 mmol) in DCM (200 mL) dropwise, and the resulting mixture was stirred at 20 °C for 1 h. The reaction was cooled to -10 °C, and a solution of Intermediate 3E (20 g, 103 mmol) in DCM (200 mL) was added dropwise. The resulting mixture was stirred at 20 °C for 1 h, then diluted with aqueous citric acid (10%) to pH=5 and extracted with DCM (3*300 mL). The combined organic extract was washed with brine (2*200 mL), dried over anydrous sodium sulfate, filtered, and concentrated to afford crude Intermediate 3F (22 g) as yellow oil.¹H NMR (400 MHz, CDCl₃) δ: 5.29 - 4.97 (m, 2H), 4.86 - 4.57 (m, 2H), 4.42 - 4.10 (m, 3H), 1.52 (s, 9H). Synthesis of Intermediate 3G [0176] To a solution of Intermediate 3F (22 g, 91.9 mmol) in MeCN (440 mL) under nitrogen was added RuCl₃ (191 mg, 919 umol) and a solution of NaIO₄ (19.7 g, 91.9 mmol) in water (220 mL) dropwise. The resulting mixture was stirred at 20 °C for 1 h, then filtered, and the filter cake was washed with DCM (300 mL). The filtrate was diluted with water (300 mL) and extracted with DCM (800 mL). The combined organic extract was washed with water (2*300 mL), brine (2*200 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford crude Intermediate 3G (17.5 g) as a yellow solid.¹H NMR (400 MHz, CDCl3) δ: 4.73-4.53 (m, 5H), 1.57 (s, 9H). Synthesis of Intermediate 3H [0177] Two batches were conducted in parallel. To a solution of Intermediate 1J (20.0 g, 70.7 mmol) in tert-butanol (400 mL) and glycol (400 mL) was added N-methyl-1-phenyl- methanamine (42.9 g, 354 mmol). The resulting mixture was stirred at 50 °C for 16 h, then concentrated to remove t-BuOH. The residue was purified by flash column chromatography on silica (petroleum ether: ethyl acetate = 30:1 to 5:1) to afford Intermediate 3H (40 g) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ: 7.40 (d, J = 9.2 Hz, 1H), 7.35-7.21 (m, 5H), 6.67 (d, J = 9.2 Hz, 1H), 4.87 (s, 2H), 3.87 (t, J = 6.0 Hz, 2H), 3.11 (s, 3H), 2.91 (t, J = 6.0 Hz, 2H), 1.48 (s, 9H). Synthesis of Intermediate 3I [0178] To a solution of Intermediate 3H (28.0 g, 76.2 mmol) in DCM (300 mL) at 0 °C was added TFA (158 g, 1.39 mol) dropwise. The resulting mixture was stirred at 20 °C for 1 h, then concentrated. The residue was diluted with DCM (200 mL), adjusted to pH 8 with saturated aqueous Na₂CO₃, and extracted with DCM (2*200 mL). The combined organic extract was washed with brine (400 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford Intermediate 3I (17.5 g) as a yellow solid.¹H NMR (400 MHz, DMSO-d6) δ: 7.83 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.33-7.20 (m, 5H), 6.58 (d, J = 8.8 Hz, 1H), 4.84 (s, 2H), 3.38-3.35 (m, 2H), 3.07 (s, 3H), 2.81 (t, J = 6.8 Hz, 2H). Synthesis of Intermediate 3J [0179] To a solution of Intermediate 3G (11.0 g, 43.1 mmol) in DMF (220 mL) at 0 °C was added NaH (60% w/w, 2.30 g, 57.4 mmol) in portions, and the resulting mixture was stirred at 0 °C for 30 min. Then Intermediate 3I (7.68 g, 28.7 mmol) was added in portions. The resulting mixture was stirred at 20 °C for 2 h, then quenched with saturated aqueous NH₄Cl (80 mL) at 0 °C, diluted with water (300 mL) and ethyl acetate (100 mL), and extracted with ethyl acetate (2*200 mL). The combined organic extract was washed with water (2*200 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica (DCM / MeOH = 50:1 to 20:1) to afford Intermediate 3J (9.7 g) as a yellow oil.¹H NMR (400 MHz, DMSO-d6) δ: 7.87 (d, J = 8.8 Hz, 1H), 7.33-7.29 (m,2H), 7.24-7.19 (m,3H), 6.94 (d, J = 8.8 Hz, 1H), 6.25 (d, J = 8.8 Hz, 1H), 4.86 (s, 2H), 4.50- 4.31 (m, 2H), 3.59-3.54 (m, 4H), 3.08 (s, 3H), 1.32 (s, 9H). Synthesis of Intermediate 3K [0180] Two batches were conducted in parallel. To a solution of Intermediate 3J (6 g, 13.6 mmol) in H₂SO₄ (60 mL) at 0 °C was added KNO₃ (5.50 g, 54.4 mmol) in portions, and the resulting mixture was stirred at 20 °C for 3 h. The two batches were poured into ice-water (1 L) and washed with ethyl acetate (2*300 mL). The aqueous phase was slowly basified to pH 9-10 using Na2CO3, and then THF (1.2 L) and Boc2O (3.55 g, 16.27 mmol) were added. The resulting mixture was stirred at 25 °C for 16 h, then extracted with ethyl acetate (2*2 L). The combined organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 10:1 to 1:1) to afford Intermediate 3K (4.13 g) as a yellow solid.¹H NMR (400 MHz, DMSO-d6) δ: 8.86 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 6.98 (d, J = 8.8 Hz, 1H), 4.45 (d, J = 5.6 Hz, 1H), 4.35 (d, J = 5.2 Hz, 1H), 3.68-3.32 (m, 4H), 3.08 (s, 3H), 3.07-3.02 (m, 2H), 1.31 (s, 9H). Synthesis of Intermediate 3L [0181] To a solution of Intermediate 3K (10.0 g, 22.6 mmol) in methanol (200 mL) was added a solution of NH4Cl (12.1 g, 226 mmol) in water (50 mL), followed by portionwise addition of zinc powder (14.5 g, 226 mmol), and the resulting mixture was stirred at rt for 2 h. The solids were filtered out and the filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography on C18 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 0% B to 50% B) to afford Intermediate 3L (7.6 g) as a light yellow solid. LCMS (ESI, m/z): 368 [M+H]⁺. Synthesis of Example 3 [0182] Example 3 (88.6 mg) was prepared as a white solid from Intermediate 3L and Intermediate 1I by using a similar synthetic protocol as that of Example 1.¹H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.31 (s, br, 3H), 8.07 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.29 (s, 1H), 7.23 (d, J = 8.0 Hz, 1H), 5.17 - 5.13 (m, 1H), 4.91 - 4.78 (m, 1H), 4.81 - 4.50 (m, 3H), 4.02 (s, 3H), 3.77 - 3.73 (m, 5H), 3.35 - 3.31 (m, 2H), 1.97 - 1.93 (m, 1H), 1.70 - 1.66 (m, 2H), 1.46 - 1.44 (m, 4H), 1.42 - 1.27 (m, 4H), 1.21 (s, 3H), 1.17 - 1.13 (m, 2H), 0.95 (s, 3H). LCMS (ESI, m/z): 589 [M+H]⁺. LCMS RT: 1.312 min (Method B2). Example 4. (R)-1²-(6-((S)-2-amino-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H- imidazo[4,5-g]isoquinolin-2-yl)-2,5,5-trimethyl-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one

[0183] To a solution of 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one (1.6 g, 10 mmol) in DMF (100 mL) at 0 °C under nitrogen was added NaH (600 mg, 15 mmol) in portions, and the resulting mixture was stirred at rt for 0.5 h. The reaction was cooled to 0 °C, and Intermediate 3G (3.1 g, 12 mmol) was added in portions. The resulting mixture was stirred at rt for 2 h, then quenched with water (300 mL) and extracted with ethyl acetate (300 mL). The combined organic extract was washed with water (2*300 mL) and brine (2*300 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 1:1) to afford Intermediate 4A (1.0 g) as a yellow solid. LCMS (ESI, m/z): 341 [M+H]⁺. Synthesis of Intermediate 4B [0184] To a solution of Intermediate 4A (1.0 g, 2.9 mmol) in MeCN (30 mL) at rt was added methylamine (2 M in THF, 1.5 eq), and the resulting mixture was stirred at rt for 2 h. The solution was concentrated under vacuum, and the crude product was purified by flash column chromatography on silica (DCM / MeOH = 10:1) to afford Intermediate 4B (1.0 g) as a light yellow solid. LCMS (ESI, m/z): 352 [M+H]⁺. Synthesis of Intermediate 4C [0185] To a solution of Intermediate 4B (1.0 g, 2.9 mmol) in H₂SO₄ (10 mL) at 0 °C was added KNO₃ (1.17 g, 11.6 mmol) in portions, and the resulting mixture was stirred at rt for 3 h. The mixture was poured into ice-water (50 mL) and washed with ethyl acetate (2*30 mL). The aqueous phase was basified to pH 9-10 with saturated aqueous Na2CO3, and then THF (50 mL) and Boc₂O (759 mg, 3.5 mmol) were added. The resulting mixture was stirred at rt for 16 h, then extracted with ethyl acetate (2*150 mL), and the combined organic extract was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 1:2) to afford Intermediate 4C (800 mg) as a yellow solid. LCMS (ESI, m/z): 397 [M+H]⁺. Synthesis of Intermediate 4D [0186] To a solution of Intermediate 4C (500 mg, 1.26 mmol) and NH₄Cl (510 mg, 9.53 mmol) in methanol (9 mL) and water (3 mL) was added zinc powder (620 mg, 9.48 mmol) portionwise, and the resulting mixture was stirred for at rt 2 h. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on C18 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 0% B to 50% B) to afford Intermediate 4D (400 mg) as a white solid. LCMS (ESI, m/z): 367 [M+H]⁺. Synthesis of Example 4 [0187] Example 4 was prepared as a white solid from Intermediate 4D and Intermediate 1I by using a similar synthetic protocol as that of Example 2.¹H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 3H), 8.27 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 7.2 Hz, 1H), 7.60 (s, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 5.19 - 5.09 (m, 1H), 4.94 - 4.47 (m, 4H), 3.96 (s, 3H), 3.85 - 3.79 (m, 2H), 3.70 - 3.65 (m, 3H), 3.23 - 3.21 (m, 2H), 1.99 - 1.89 (m, 1H), 1.75 -1.56 (m, 2H), 1.52 - 1.28 (m, 8H), 1.21 (s, 3H), 1.14 - 1.03 (m, 2H), 0.94 (s, 3H). LCMS (ESI, m/z): 588 [M+H]⁺ LCMS RT: 1.255 min (Method B2).

Example 5. (R)-1²-(1-cyclopropyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro- 1H-imidazo[4,5-g]isoquinolin-2-yl)-2,5,5-trimethyl-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one

[0188] To a solution of Intermediate 1I (200 mg, 0.56 mmol) in THF (8 mL) at 0 °C under nitrogen was added LiAlH₄ (2.5 M in THF, 1.1 mL, 2.8 mmol) dropwise, and the resulting mixture was stirred at rt for 2 h. The reaction was then quenched with water (0.1 mL), saturated aqueous NaHCO₃ (0.3 mL), and water (0.1 mL) in sequence and stirred at rt for 20 min. Then the mixture dried over anhydrous sodium sulfate, the solids were filtered out, and the filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography on C18 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 0% B to 100% B) to afford Intermediate 5A (150 mg) as a yellow solid. LCMS (ESI, m/z): 344 [M+H]⁺ . Synthesis of Intermediate 5B [0189] To a solution of Intermediate 5A (150 mg, 0.44 mmol) in DCM (5 mL) at rt was added MnO₂ (380 mg, 4.37 mmol), and the resulting mixture was stirred at rt for 2 h. The solids were filtered out and the filtrate was concentrated under vacuum. The crude product was purified by Prep-TLC (petroleum ether / ethyl acetate = 3:1) to afford Intermediate 5B (120 mg) as a yellow solid. LCMS (ESI, m/z): 342 [M+H]⁺ . Synthesis of Intermediate 5C [0190] To a solution of Intermediate 2D (2.4 g, 5.86 mmol) in DMF (60 mL) under nitrogen were added Cs2CO3 (5.72 g, 17.6 mmol) and cyclopropylamine (670 mg, 11.7 mmol), and the resulting mixture was stirred at rt for 1 h. The reaction was then quenched with water (200 mL) and extracted with ethyl acetate (2*200 mL). The combined organic extract was washed with water (2*400 mL) and brine (2*400 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 1:2) to afford Intermediate 5C (1.6 g) as a yellow solid. LCMS (ESI, m/z): 447 [M+H]⁺ . Synthesis of Intermediate 5D [0191] To a reaction flask under nitrogen was added Pd/C (480 mg, 4.53 mmol), followed by ethyl acetate (100 mL), DCM (5 mL), and Intermediate 5C (1.6 g, 3.58 mmol). The reaction flask was degassed and recharged with nitrogen (3x) followed by hydrogen (3x). The resulting mixture was stirred at room temperature for 4 h under hydrogen, then the solids were filtered out and the filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography on C18 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 0% B to 60% B) to afford Intermediate 5D (600 mg) as a yellow solid. LCMS (ESI, m/z): 417 [M+H]⁺ . Synthesis of Intermediate 5E [0192] To a solution of Intermediate 5B (80 mg, 0.23 mmol) and Intermediate 5D (97.6 mg, 0.23 mmol) in DMF (1.5 mL) and water (0.05 mL) was added oxone (144 mg, 0.23 mmol). The resulting solution was stirred at rt for 2 h, then diluted with water (10 mL) and extracted with ethyl acetate (2*10 mL). The combined organic extract was washed with water (2*20 mL) and brine (2*20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by Prep-TLC (petroleum ether / ethyl acetate = 1:2) to afford Intermediate 5E (80 mg) as a white solid. LCMS (ESI, m/z): 738 [M+H]⁺ . Synthesis of Example 5 [0193] To a solution of Intermediate 5D (100 mg, 0.14 mmol) in DCM (5 mL) was added TFA (1 mL). The resulting mixture was stirred at rt for 1 h, then concentrated under vacuum. The crude product was purified by Prep-HPLC (Method A, RT: 7.8 min). The pure fractions were concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to afford Example 5 (69.1 mg) as a white solid.¹H NMR (400 MHz, DMSO-d₆+D₂O) δ 8.26 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.28 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 5.18 - 5.10 (m, 1H), 4.96 - 4.87 (m, 1H), 4.69 - 4.58 (m, 1H), 4.03 - 3.91 (m, 3H), 3.79 - 3.70 (m, 3H), 3.68 - 3.57 (m, 3H), 3.56 - 3.49 (m, 1H), 3.34 - 3.19 (m, 3H), 3.13 - 3.04 (m, 1H), 1.97 - 1.85 (m, 1H), 1.68 - 1.63 (m, 1H), 1.52 - 1.41 (m, 4H), 1.39 - 1.28 (m, 5H), 1.29 - 1.22 (m, 4H), 1.17 - 1.05 (m, 2H), 1.03 - 0.88 (m, 5H), 0.46 -0.42 (m, 1H). LCMS (ESI, m/z): 638 [M+H]⁺. LCMS RT: 1.004 min (Method D1). Example 6. (R)-1²-(9-fluoro-1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-2,5,5-trimethyl-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one

Synthesis of Intermediate 6A [0194] To a solution of 2-(3-chloro-2-fluoro-phenyl)acetonitrile (10.0 g, 58.9 mmol) in THF (134 mL) at rt under nitrogen was added BH₃ (1 M in THF, 134 mL, 134 mmol). The resulting mixture was stirred at 70 °C for 2 h in a sealed vessel, then added dropwise into methanol at 0 °C and stirred at 0 °C for 20 min. The mixture was concentrated under vacuum to afford crude Intermediate 6A (5.7 g) as a yellow oil. LCMS (ESI, m/z): 174, 176 [M+H]⁺. Synthesis of Intermediate 6B [0195] To a solution of triphosgene (5.7 g, 19.5 mmol) in DCM (48 mL) at 0 °C under nitrogen was added a solution of Intermediate 6A (1.1 g, 6.50 mmol) and Et₃N (22.6 mL, 13.0 mmol) in DCM (24 mL), and the resulting mixture was stirred at rt for 2 h. The solids were filtered out and the filtrate was added dropwise into a solution of AlCl3 (5.2 g, 39.0 mmol) in DCM (50 mL) at 0 °C under nitrogen. The resulting mixture was stirred at rt overnight, then quenched with water (200 mL), acidified with aqueous HCl (4 M) until the mixture became a transparent solution, and extracted with DCM (2*200 mL). The combined organic extract was washed with brine (400 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (100% ethyl acetate) to afford Intermediate 6B (2 g) as a yellow oil. LCMS (ESI, m/z): 200, 202 [M+H]⁺ . Synthesis of Intermediate 6C [0196] To a solution of Intermediate 6B (500 mg, 2.50 mmol) in THF (25 mL) at 0 °C under nitrogen was added NaH (60% w/w, 90 mg, 3.76 mmol) in portions, and the resulting mixture was stirred at rt for 0.5 h. The reaction mixture was cooled to 0 °C, and (R)-tetrahydro- 3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1,1-dioxide (673 mg, 3.76 mmol) was added in portions. The resulting mixture was stirred at rt for 0.5 h, then quenched with saturated aqueous NH4Cl (1 mL) and directly purified by flash column chromatography on C18 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 15% B to 90% B) to afford a sulfonic acid intermediate as a yellow solid, which was added into HCl (4 M in MeOH, 10 mL) and stirred at 50 °C for 1 h in a sealed vessel. The reaction was concentrated under vacuum to afford Intermediate 6C (400 mg) as a yellow oil. LCMS (ESI, m/z): 299, 301 [M+H]⁺ . Synthesis of Intermediate 6D [0197] To a solution of Intermediate 6C (150 mg, 0.5 mmol) in H2SO4 (2 mL) at 0 °C was added KNO3 (202 mg, 2.01 mmol) portionwise, and the resulting mixture was stirred at rt for 2 h. The reaction mixture was added dropwise into ice water, stirred for 10 min, and washed with ethyl acetate (2*10 mL). The remaining aqueous phase was advanced into the next step directly without further processing. LCMS (ESI, m/z): 344, 346 [M+H]⁺ . Synthesis of Intermediate 6E [0198] The aqueous solution from the previous step was adjusted to pH 8 with saturated aqueous NaHCO₃ (10 mL), followed by addition of Boc₂O (76.4 mg, 0.35 mmol) in THF (5 mL). The resulting mixture was stirred at rt overnight, then extracted with ethyl acetate (2*40 mL). The combined organic extract was washed with brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 5:1) to afford Intermediate 6E (120 mg) as a light yellow solid. LCMS (ESI, m/z): 444, 446 [M+H]⁺ . Synthesis of Intermediate 6F [0199] To a solution of Intermediate 6E (120 mg, 0.27 mmol) and DIPEA (104 mg, 0.81 mmol) in MeCN (3 mL) was added methylamine (2 M in THF, 0.81 mL), and the resulting mixture was stirred at 50 °C overnight in a sealed vessel. The reaction mixture was purified by flash column chromatography on C18 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 5% B to 85% B in 25 min) to afford Intermediate 6F (100 mg) as a white solid. LCMS (ESI, m/z): 439 [M+H]⁺ . Synthesis of Intermediate 6G [0200] To a solution of Intermediate 6F (100 mg, 0.23 mmol) in methanol (4 mL) was added a solution of NH4Cl (122 mg, 2.28 mmol) in water (2 mL), followed by portionwise addition of zinc powder (119 mg, 1.82 mmol), and the resulting mixture was stirred at rt for 3 h. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was diluted with water (20 mL) and extracted with ethyl acetate (3*20 mL). The combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on C18 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 0% B to 60% B) to afford Intermediate 6G (75 mg) as a white solid. LCMS (ESI, m/z): 409 [M+H]⁺ . Synthesis of Example 6 [0201] Example 6 (37.8 mg) was prepared as a white solid from Intermediate 6G (75 mg, 0.18 mmol) and Intermediate 1I by using a similar synthetic protocol as that of Example 2.¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.12 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 5.12 - 5.10 (m, 1H), 4.90 - 4.80 (m, 1H), 4.49 - 4.50 (m, 1H), 4.11 (s, 3H), 3.97 - 3.89 (m, 3H), 3.78 - 3.76 (m, 2H), 3.75 - 3.63 (m, 3H), 3.48 - 3.47 (m, 1H), 3.31 - 3.28 (m, 1H), 3.21 - 3.12 (m, 2H), 3.11 - 3.00 (m, 1H), 2.55 - 2.52 (m, 1H), 1.92 - 1.89 (m, 1H), 1.71 - 1.50 (m, 2H), 1.44 (d, J = 6.8 Hz, 3H), 1.42 - 1.32 (m, 4H), 1.20 (s, 3H), 1.09 -1.02 (m, 2H), 0.93 (s, 3H). LCMS (ESI, m/z): 630 [M+H]⁺. LCMS RT: 0.735 min (Method B1). Example 7. (R)-1²-(9-methoxy-1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-2,5,5-trimethyl-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one

[0202] To a solution of Intermediate 2E (1.1 g, 2.62 mmol) in DMF (26 mL) under nitrogen was added NBS (698 mg, 3.92 mmol). The resulting mixture was stirred at rt overnight, then diluted with water (130 mL) and extracted with ethyl acetate (2*130 mL). The combined organic layer was washed with water (2*260 mL) and brine (2*260 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (100% ethyl acetate) to afford Intermediate 7A (1.05 g) as a yellow solid. LCMS (ESI, m/z): 499, 501 [M+H]⁺ . Synthesis of Intermediate 7B [0203] To a solution of Intermediate 7A (70 mg, 0.14 mmol) and Intermediate 5B (72 mg, 0.21 mmol) in ethanol (1 mL) and water (0.5 mL) was added Na₂S₂O₄ (97 mg, 0.56 mmol). The resulting mixture was stirred at rt for 6 h, then diluted with water (5 mL) and extracted with ethyl acetate (2*5 mL). The combined organic extract was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (DCM / MeOH = 20:1) to afford Intermediate 7B (80 mg) as a light yellow solid. LCMS (ESI, m/z): 790, 792 [M+H]⁺ . Synthesis of Intermediate 7C [0204] To a solution of Intermediate 7B (80 mg, 0.10 mmol) and KOH (39 mg, 0.30 mmol) in methanol (2.5 mL) and 1,4-Dioxane (2.5 mL) under nitrogen was added Pd2(dba)3 (18 mg, 0.02 mmol) and t-BuBrettPhos (33 mg, 0.04 mmol). The resulting mixture was stirred at 100 °C for 2 h in a sealed vessel, then diluted with water (15 mL) and extracted with ethyl acetate (2*15 mL). The combined organic extract was washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 4:1) to afford Intermediate 7C (14 mg) as a light yellow solid. LCMS (ESI, m/z): 742 [M+H]⁺ . Synthesis of Example 7 [0205] To a solution of Intermediate 7C (14 mg, 0.02 mmol) in DCM (2 mL) was added TFA (0.5 mL). The resulting mixture was stirred at rt for 1 h, then concentrated under vacuum. The crude product was purified by Prep-HPLC (Method E1, RT: 8.63 min). The pure fractions were concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to afford Example 7 (6.2 mg) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.15 - 8.82 (m, 2H), 8.07 - 8.05 (m, 2H), 7.83 (d, J = 7.2 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.09 (s, 1H), 5.13 - 5.10 (m, 1H), 4.86 - 4.81 (m, 1H), 4.47 - 4.46 (m, 1H), 4.09 (s, 3H), 4.08 - 4.02 (m, 2H), 3.91 (s, 3H), 3.90 - 3.88 (m, 2H), 3.73 - 3.61 (m, 4H), 3.59 - 3.05 (m, 5H), 1.92 - 1.88 (m, 1H), 1.72 - 1.66 (m, 2H), 1.59 - 1.57 (m, 3H), 1.46 - 1.35 (m, 5H), 1.32 (s, 3H), 1.23 - 1.06 (m, 2H), 0.94 (s, 3H). LCMS (ESI, m/z): 642 [M+H]⁺. LCMS RT: 1.459 min (Method B2). Example 8. (R)-1²-(1,9-dimethyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro- 1H-imidazo[4,5-g]isoquinolin-2-yl)-2,5,5-trimethyl-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one

[0206] To a solution of Intermediate 7B (70 mg, 0.09 mmol) and 2,4,6-trimethyl- 1,3,5,2,4,6-trioxatriborinane (11 mg, 0.09 mmol) in 1,4-Dioxane (3 mL) under nitrogen were added PEPPSI-IPr (12 mg, 0.02 mmol) and K₂CO₃ (36 mg, 0.27 mmol). The resulting mixture was stirred at 80 °C for 10 h, then diluted with water (9 mL) and extracted with ethyl acetate (2*9 mL). The combined organic extract was washed with water (18 mL) and brine (18 mL), then dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 1:2) to afford Intermediate 8A (40 mg) as a light yellow solid. LCMS (ESI, m/z): 726 [M+H]⁺ . Synthesis of Example 8 [0207] To a solution of Intermediate 8A (40 mg, 0.05 mmol) in DCM (2 mL) was added TFA (0.5 mL). The resulting mixture was stirred at rt for 1 h, then concentrated under vacuum. The crude product was purified by Prep-HPLC (Method F, RT: 8.7 min). The pure fractions were concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to afford Example 8 (15.2 mg) as a white solid. LCMS (ESI, m/z): 626 [M+H]⁺. LCMS RT: 1.377 min (Method B2).

Example 9. (R)-2-methyl-1²-(1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1¹H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridina- 5(1,2)-benzenacyclodecaphan-4-one Synthesis of Intermediate 9A [0208] To a solution of Intermediate 1E (5 g, 14.4 mmol) in THF (150 mL) at 0 °C under nitrogen was added LiAlH4 (2.5 M in THF, 29 mL) dropwise, and the resulting mixture was stirred at rt for 2 h. The reaction was then quenched with water (2.7 mL), saturated aqueous NaHCO3 (8.1 mL), and water (2.7 mL) in sequence and stirred at rt for 20 min. Then the mixture was dried over anhydrous sodium sulfate, the solids were filtered out, and the filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 1:1) to afford Intermediate 9A (4 g) as a white solid. LCMS (ESI, m/z): 292 [M+H]⁺ . Synthesis of Intermediate 9B [0209] To a solution of Intermediate 9A (4 g, 13.7 mmol) in DCM (150 mL) at rt was added MnO2 (11.9 g, 137 mmol), and the resulting mixture was stirred for 2 h. The solids were filtered out and the filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 3:1) to afford Intermediate 9B (3.5 g) as a light yellow solid. LCMS (ESI, m/z): 290 [M+H]⁺ . Synthesis of Intermediate 9C [0210] To a solution of Intermediate 9B (1.4 g, 4.8 mmol) and Intermediate 2E (2.1 g, 4.8 mmol) in ethanol (30 mL) and water (15 mL) was added Na2S2O4 (2.1 g, 24.2 mmol). The resulting mixture was stirred at 90 °C overnight, then diluted with water (150 mL) and extracted with ethyl acetate (2*150 mL). The combined organic extract was washed with water (300 mL) and brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (DCM / MeOH = 15:1) to afford Intermediate 9C (1.5 g) as a yellow solid. LCMS (ESI, m/z): 660 [M+H]⁺. Synthesis of Intermediate 9D [0211] To a solution of Intermediate 9C (120 mg, 0.18 mmol) in DMF (2 mL) under nitrogen were added Cs₂CO₃ (177 mg, 0.55 mmol) and tert-butyl 2-(5-(tosyloxy)pentyl)benzoate* (91 mg, 0.22 mmol). The resulting mixture was stirred at 50 °C for 2 h, then diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with water (2*10 mL) and brine (2*10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 4:1) to afford Intermediate 9D (100 mg) as a light yellow solid. LCMS (ESI, m/z): 907 [M+H]⁺. *prepared according to similar synthetic protocols as described in WO2021222353. Synthesis of Intermediate 9E [0212] To a solution of Intermediate 9D (100 mg, 0.11 mmol) in DCM (2 mL) was added TFA (0.5 mL). The resulting mixture was stirred at rt for 16 h, then concentrated under vacuum to afford Intermediate 9E (70 mg) as a white solid. LCMS (ESI, m/z): 650 [M+H]⁺. Synthesis of Example 9 [0213] To a solution of Intermediate 9E (70 mg, 0.11 mmol) and DIPEA (42 mg, 0.32 mmol) in DMF (2 mL) at rt under nitrogen was added HATU (62 mg, 0.16 mmol). The mixture was stirred at rt for 1 h, then concentrated under vacuum. The crude product was purified by Prep-HPLC (Method G, RT: 8.57 min). The pure fractions were concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to afford Example 9 (35 mg) as a yellow solid.¹H NMR (400 MHz, DMSO-d6) δ 9.09 - 9.03 (m, 1H), 9.00 - 8.84 (m, 2H), 8.26 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.35 - 7.29 (m, 2H), 7.24 - 7.17 (m, 4H), 5.20 - 5.16 (m, 1H), 4.92 - 4.88 (m, 1H), 4.81- 4.78 (m, 1H), 4.02- 3.88 (m, 6H), 3.74 - 3.71 (m, 2H), 3.69 - 3.61 (m, 3H), 3.59 - 3.56 (m, 1H), 3.35 - 3.20 (m, 3H) 3.12 - 3.05 (m, 1H), 2.40 - 2.33 (m, 2H), 2.21 - 2.13 (m, 1H), 1.61 - 1.44 (m, 5H), 1.32 - 1.05 (m, 2H), 0.62 - 0.43 (m, 1H). LCMS (ESI, m/z): 632 [M+H]⁺. LCMS RT: 2.968 min (Method H). Example 10. (R)-2-methyl-1²-(1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1¹H-6-oxa-3-aza-1(6,1)-pyrrolo[2,3- b]pyridina-5(1,2)-benzenacyclodecaphan-4-one Synthesis of Example 10 [0214] Example 10 was prepared as a white solid from Intermediate 9C and tert-butyl 2- (4-bromobutoxy)benzoate (WO2021222353) by using a similar synthetic protocol as that of Example 9.¹H NMR (400 MHz, DMSO-d6) δ 9.75 (d, J = 6.8 Hz, 1H), 9.13 (s, br, 1H), 8.96 (s, br, 1H), 8.31 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.11 - 8.08 (m, 1H), 7.64 (s, 1H), 7.56 - 7.48 (m, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.16 (s, 1H), 7.01 - 7.08 (m, 1H), 5.40 - 5.30 (m, 1H), 4.96 - 4.88 (m, 1H), 4.51 - 4.41(m, 2H), 4.35 - 4.28 (m, 1H), 4.11 - 4.08 (m, 1H), 4.03 (s, 3H), 3.99 - 3.85 (m, 2H), 3.79 - 3.49 (m, 3H), 3.39 - 3.29 (m, 3H), 3.28 - 3.19 (m, 3H), 3.14 - 3.02 (m, 1H), 2.68 - 2.58 (m, 1H), 2.31 - 2.28 (m, 1H), 1.96 - 1.93 (m, 2H), 1.57 (d, J = 6.4 Hz, 3H). LCMS (ESI, m/z): 634 [M+H]⁺. LCMS RT: 1.630 min (Method D2).

Example 11. (R)-2-methyl-1²-(1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one Synthesis of Intermediate 11A [0215] To a solution of tert-butyl 8-hydroxyoctanoate (500 mg, 2.31 mmol) in DCM (20 mL) at 0 °C under nitrogen were added Et3N (1.15 g, 11.4 mmol), DMAP (60 mg, 0.49 mmol) and TsCl (1.30 g, 6.81 mmol) in portions. The resulting mixture was stirred at rt overnight, then diluted with water (20 mL) and extracted with DCM (2*20 mL). The combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by Prep-TLC (petroleum ether / ethyl acetate = 5:1) to afford Intermediate 11A (600 mg) as a colorless oil. LCMS (ESI, m/z): 371 [M+H]⁺ . Synthesis of Example 11 [0216] Example 11 was prepared as a white solid from Intermediate 9C and Intermediate 11A by using a similar synthetic protocol as that of Example 9.¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (s, br, 1H), 8.88 (s, br, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.27 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.15 (s, 1H), 5.25 - 5.20 (m, 1H), 5.03 - 4.99 (m, 1H), 4.71 - 4.69 (m, 1H), 4.05 - 4.00 (m, 1H), 3.99 (s, 3H), 3.98 - 3.88 (m, 2H), 3.74 - 3.63 (m, 2H), 3.61 - 3.53 (m, 5H), 3.26 - 3.20 (m, 2H), 3.12 - 3.02 (m, 2H), 2.10 - 2.06 (m, 2H), 1.68-1.66 (m, 1H), 1.58 - 1.33 (m, 6H), 1.17 - 1.11 (m, 2H), 1.03 - 0.97 (m, 2H), 0.69 - 0.58 (m, 1H). LCMS (ESI, m/z): 584 [M+H]⁺. LCMS RT: 0.781 min (Method D1).

Example 12. (R)-2-methyl-l²-(l-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8- tetrahydro-lH-imidazo[4,5-g]isoquinolin-2-yl)-l¹H-3-aza-l(6,l)-pyrrolo[2,3-b]pyridina- 5(2,3)-pyrazinacyclodecaphan-4-one

Synthesis of Intermediate 12A

[0217] A mixture of (Z)-tert-butyl N,N'-diisopropylcarbamimidate (329 pL, 1.478 mmol) and 3-bromopyrazine-2-carboxylic acid (100 mg, 0.493 mmol) in THF (2.2 mL) was brought to 60 °C and stirred overnight. The reaction mixture was then diluted with EtOAc, washed with water (2X), brine, dried over MgSO4, filtered and concentrated in vauco. The crude product was purified by column chromatography on silica (0 to 100% EtOAc in hexanes) to afford Intermediate 12A (112.7 mg). *H NMR (400 MHz, DMSO-d6) δ 8.79 - 8.71 (m, 1H), 8.70 - 8.63 (m, 1H), 1.59 (s, 9H).

Synthesis of Intermediate 12B

[0218] Intermediate 12B was synthesized from Intermediate 12A according to similar synthetic protocols as described in WO2021222353 for the chloride variant of Intermediate 12A. LCMS (ESI, m/z): 421 [M+H]⁺ .

Synthesis of Intermediate 12C

[0219] A mixture of Intermediate 9C (50 mg, 0.076 mmol), Intermediate 12A-2 (38.2 mg, 0.091 mmol), and cesium carbonate (54.3 mg, 0.167 mmol) in DMF (997 pL) was brought to 65 °C and stirred overnight. After coming to rt, the reaction mixture was diluted with ethyl acetate, washed with water (2X), brine, dried over MgSCM, filtered and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (DCM / MeOH) to afford Intermediate 12C (65.5 mg). LCMS (ESI, m/z): 908 [M+H]⁺ . Synthesis of Intermediate 12D [0220] To a solution of Intermediate 12C (65.5 mg, 0.072 mmol) in DCM (160 µL) was added HCl (4.0 M in dioxane, 721 µL, 2.89 mmol). The resulting mixture was stirred at rt for 1 h, then concentrated to dryness under a stream of nitrogen to afford crude Intermediate 12D. LCMS (ESI, m/z): 652 [M+H]⁺ . Synthesis of Example 12 [0221] To a mixture of Intermediate 12D and HATU (82 mg, 0.216 mmol) in DMF (2.9 mL) was added DIPEA (63 µL, 0.36 mmol). The resulting mixture was stirred at rt for 1 h, then concentrated to ~2 mL total volume under a stream of nitrogen. The remaining mixture was filtered and the filtrate was purified via Prep-HPLC (Method I1). Fractions containing the desired product were dried under vacuum. The purified material was then diluted with 3 mL of a 1:1 mixture of ethylene dichloride and methanol, treated with Si-Pyridine, and shaken for a minimum of 2 h. The resulting mixture was filtered and dried under vacuum to afford Example 12 (18.9 mg). LCMS (ESI, m/z): 634.1 [M+H]⁺. LCMS RT: 1.27 min (Method J). Example 13. (R)-2-methyl-1²-(1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1¹H-7,10-dioxa-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacyclododecaphan-4-one O H N N N O Synthesis o

[0222] Example 13 was prepared from Intermediate 9C and tert-butyl 3-(2-(2- bromoethoxy)ethoxy)propanoate by using a similar synthetic protocol as that of Example 9. LCMS (ESI, m/z): 602.2 [M+H]⁺. LCMS RT: 1.04 min. (Method J). Example 14. (R)-1²-(7-((S)-2-amino-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H- imidazo[4,5-b][1,6]naphthyridin-2-yl)-5⁵-fluoro-2-methyl-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridina-5(4,3)-pyridinacyclodecaphan-4-one

[0223] To a solution of tert-butyl 3-fluoro-5-(5-hydroxypentyl)pyridine-4-carboxylate* (200 mg, 0.71 mmol) in DCM (6 mL) was added Et₃N (273 mg, 2.12 mmol). The resulting mixture was cooled to 0 °C under nitrogen. Then TsCl (202 mg, 1.06 mmol) and DMAP (17 mg, 0.14 mmol) were added portionwise, and the resulting mixture was stirred overnight at rt. The reaction was diluted with saturated aqueous NH₄Cl (15 mL) at 0 °C and extracted with DCM (3*15 mL). The combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum at 0 °C. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 3:1) to afford Intermediate 14A (225 mg) as a colorless oil. LCMS (ESI, m/z): 438 [M+H]⁺. *prepared according to similar synthetic protocols as described in WO2021222353. Synthesis of Intermediate 14B [0224] To a solution of Intermediate 1E (1.0 g, 2.88 mmol) in DMF (20 mL) under nitrogen were added Cs2CO3 (2.8 g, 8.59 mmol) and Intermediate 14A (1.3 g, 2.97 mmol). The resulting mixture was stirred at 50 °C for 3 h, then diluted with water (100 mL) and extracted with ethyl acetate (2*100 mL). The combined organic extract was washed with water (2*200 mL) and brine (2*200 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 2:1) to afford Intermediate 14B (1.3 g) as a yellow oil. LCMS (ESI, m/z): 613 [M+H]⁺ . Synthesis of Intermediate 14C [0225] To a solution of Intermediate 14B (1.0 g, 1.63 mmol) in DCM (20 mL) was added TFA (5 mL). The resulting mixture was stirred at rt overnight, then concentrated under vacuum to afford crude Intermediate 14C (600 mg) as a yellow oil. LCMS (ESI, m/z): 457 [M+H]⁺ . Synthesis of Intermediate 14D [0226] To a solution of Intermediate 14C (1.1 g, 2.41 mmol) and DIPEA (5 g, 38.5 mmol) in DCM (20 mL) at rt under nitrogen was added HATU (1.4 g, 3.68 mmol). The resulting mixture was stirred at rt for 16 h, then diluted with water (50 mL) and extracted with DCM (2*50 mL). The combined organic extract was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate =3:1) to afford Intermediate 14D (400 mg) as a white solid. LCMS (ESI, m/z): 439 [M+H]⁺ . Synthesis of Intermediate 14E [0227] To a solution of Intermediate 14D (350 mg, 0.80 mmol) in methanol (6 mL) and water (3 mL) was added NaOH (250 mg, 6.25 mmol), and the resulting mixture was stirred at 50 °C for 0.5 h. The reaction mixture was acidified to pH 2 with aqueous HCl (1 M), stirred at rt for 0.5 h, then diluted with water (20 mL) and extracted with ethyl acetate (2*20 mL). The combined organic extract was washed with water (2*40 mL) and brine (2*40 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford crude product Intermediate 14E (300 mg) as a white solid. LCMS (ESI, m/z): 397 [M+H]⁺ . Synthesis of Example 14 [0228] Example 14 was prepared as a white solid from Intermediate 14E and Intermediate 3L by using a similar synthetic protocol as that of Example 1.¹H NMR (400 MHz, DMSO-d₆) δ 9.48 (d, J = 7.6 Hz, 1H), 8.50 (d, J = 9.2 Hz, 2H), 8.34 (s, 1H), 8.29 - 8.24 (m, 3H), 8.13 (d, J = 8.0 Hz, 1H), 7.32 - 7.29 (m, 2H), 5.33 - 5.25 (m, 1H), 4.98 - 4.80 (m, 2H), 4.68 - 4.59 (m, 2H), 4.03 (s, 3H), 3.88 - 3.81 (m, 2H), 3.80 - 3.73 (m, 3H), 3.50 - 3.45 (m, 2H), 2.36 - 2.33 (m, 1H), 2.22 - 2.11 (m, 1H), 1.59 - 1.47 (m, 6H), 1.35 - 1.14 (m, 2H), 0.45 - 0.39 (m, 1H). LCMS (ESI, m/z): 628 [M+H]⁺. LCMS RT: 1.205 min (Method K1). Example 15. (R)-1²-(6-((S)-2-amino-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H- imidazo[4,5-g]isoquinolin-2-yl)-5⁵-fluoro-2-methyl-1¹H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridina- 5(4,3)-pyridinacyclodecaphan-4-one Synthe [022

] p p p t

ermediate 4D by using a similar synthetic protocol as that of Example 2.¹H NMR (400 MHz, DMSO-d6) δ 9.48 (d, J = 7.2 Hz, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 8.28 - 8.23 (m, 4H), 8.11 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 5.32 - 5.23 (m, 1H), 4.94 - 4.61 (m, 4H), 3.98 (s, 3H), 3.87 - 3.81 (m, 3H), 3.78 - 3.76 (m, 2H), 3.28 - 3.17 (m, 2H), 2.33 - 2.39 (m, 1H), 2.17 - 2.11 (m, 1H), 1.58 - 1.41 (m, 6H), 1.28 - 1.17 (m, 2H), 0.51 - 0.35 (m, 1H). LCMS (ESI, m/z): 627 [M+H]⁺. LCMS RT: 0.664 min (Method K2). Example 16. (R)-1²-(1-cyclopropyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro- 1H-imidazo[4,5-g]isoquinolin-2-yl)-5⁵-fluoro-2-methyl-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridina-5(4,3)-pyridinacyclodecaphan-4-one Synthes

[0230] Example 16 was prepared as a white solid from Intermediate 14D and Intermediate 5D by using a similar synthetic protocol as that of Example 5.¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (d, J = 8.0 Hz, 1H), 9.16 - 8.89 (m, 2H), 8.48 (s, 1H), 8.33 (s, 1H), 8.23 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.35 (s, 1H), 7.26 (d, J = 8.0 Hz, 1H), 5.30 - 5.22 (m, 1H), 4.99 - 4.89 (m, 2H), 4.00 - 3.82 (m, 4H), 3.80 - 3.69 (m, 2H), 3.64 - 3.57 (m, 3H), 3.52 - 3.47 (m, 1H), 3.28 - 3.15 (m, 3H), 3.12 - 3.01 (m, 1H), 2.49 - 2.42 (m, 1H), 2.40 - 2.31 (m, 1H), 2.14 - 2.05 (m, 1H), 1.49 (d, J = 7.2 Hz, 3H), 1.46 - 1.35 (m, 2H), 1.34 - 1.23 (m, 2H), 1.21 - 1.09 (m, 2H), 1.04 - 0.95 (m, 1H), 0.43 - 0.32 (m, 2H). LCMS (ESI, m/z): 677 [M+H]⁺. LCMS RT: 0.635 min (Method B1). Example 17. (R)-5⁵-fluoro-2-methyl-1²-(1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo- 5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridina-5(4,3)-pyridinacyclodecaphan-4-one Synthesi [0231

] Example 17 was prepared as a white solid from Intermediate 14E and Intermediate 2F by using a similar synthetic protocol as that of Example 2.¹H NMR (400 MHz, DMSO- d6+D2O) δ 9.49 (d, J = 8.0 Hz 1H), 8.48 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 8.11 (d, J = 8.0 Hz 1H), 7.62 (s, 1H), 7.28 (d, J = 8.0 Hz 1H), 7.20 (s, 1H), 5.29 - 5.26 (m, 1H), 4.69 - 4.89 (m, 1H), 4.78 - 4.74 (m, 1H), 4.00 - 3.93 (m, 6H), 3.74 - 3.69 (m, 2H), 3.60 - 3.57 (m, 3H), 3.57 - 3.52 (m, 1H), 3.32 - 3.06 (m, 4H), 2.52 - 2.37 (m, 2H), 2.12 - 2.08 (m, 1H), 1.49 - 1.44 (m, 5H), 1.28 - 1.12 (m, 2H), 0.45-0.41 (m, 1H). LCMS (ESI, m/z): 651 [M+H]⁺. LCMS RT: 0.664 min (Method K2). Example 18. (5¹R,5²R,2R)-2-methyl-1²-(1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo- 5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridina-5(1,2)-cyclopropanacyclodecaphan-4-one

[0232] To a solution of (5¹R,5²R,2R,Z)-2-methyl-4-oxo-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridina-5(1,2)-cyclopropanacyclodecaphan-7-ene-1²-carbaldehyde* (80 mg, 0.25 mmol, WO2021222353) and Intermediate 2F (110 mg, 0.28 mmol) in ethanol (2 mL) and water (1 mL) was added Na₂S₂O₄ (160 mg, 0.92 mmol). The resulting mixture was stirred at 90 °C for 2 h, then cooled to rt and directly purified by flash column chromatography on C18 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 0% B to 100% B) to afford Intermediate 18A (120 mg) as a yellow solid. *Note: the cis/trans composition was not determined. LCMS (ESI, m/z): 694 [M+H]⁺ . Synthesis of Intermediate 18B [0233] To a reaction flask under nitrogen was added Pd/C (40 mg), followed by ethanol (5 mL), and Intermediate 18A (120 mg, 0.17 mmol). The reaction flask was degassed and recharged with nitrogen (3x) followed by hydrogen (3x). The mixture was stirred at rt overnight under hydrogen, then the solids were filtered out and the filtrate was concentrated under vacuum to afford crude Intermediate 18B (80 mg) as a yellow oil. LCMS (ESI, m/z): 696 [M+H]⁺ . Synthesis of Example 18 [0234] To a solution of Intermediate 18B (80 mg, 0.11 mmol) in DCM (2 mL) was added TFA (0.5 mL). The resulting mixture was stirred at rt for 1 h, then and concentrated under vacuum. The crude product was purified by Prep-HPLC (Method E2, RT: 8.68 min). The pure fractions were concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to afford Example 18 (41.1 mg) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (s, br, 1H), 8.91 (s, br , 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.28 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 5.09 - 5.01 (m, 1H), 4.87 - 4.75 (m, 2H), 4.04 - 3.85 (m, 6H), 3.84 - 3.72 (m, 3H), 3.71 - 3.63 (m, 2H), 3.36 - 3.22 (m, 2H), 3.21 - 3.17 (m, 2H), 3.14 - 3.01 (m, 1H), 1.90 - 1.84 (m, 1H), 1.72 - 1.31 (m, 9H), 1.24 - 1.17 (m, 1H), 0.99 - 0.86 (m, 1H), 0.81 - 0.61 (m, 2H), 0.49-0.46 (m, 1H). LCMS (ESI, m/z): 596 [M+H]⁺. LCMS RT: 0.619 min (Method B1).

Example 19. (R)-2'-methyl-2'-(1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)spiro[cyclopropane-1,5'-3-aza-1(6,1)- pyrrolo[2,3-b]pyridinacycloundecaphan]-4'-one

[0235] Example 19 was prepared as a white solid from Intermediate 1E, tert-butyl 1-(6- bromohexyl)cyclopropane-1-carboxylate (WO2021222353), and Intermediate 2F by using a similar synthetic protocol as that of Example 14.¹H NMR (400 MHz, DMSO-d₆+D₂O) δ 8.30 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.15 (s, 1H), 5.31 - 5.22 (m, 1H), 4.94 - 4.83 (m, 1H), 4.56 - 4.45 (m, 1H), 4.04 - 3.90 (m, 6H), 3.80 - 3.71 (m, 2H), 3.67 - 3.53 (m, 4H), 3.32 - 3.21 (m, 4H), 2.39 - 1.97 (m, 2H), 1.88 - 1.51 (m, 3H), 1.50 - 1.33 (m, 5H), 1.30 - 0.89 (m, 5H), 0.69 - 0.47 (m, 2H). LCMS (ESI, m/z): 610 [M+H]⁺. LCMS RT: 1.344 min (Method B2). Example 20. (R)-2,5,5-trimethyl-1²-(1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacyclodecaphan-4-one Synt

[0236] Example 20 was prepared as a white solid from Intermediate 1E, tert-butyl 7- bromo-2,2-dimethylheptanoate (WO2021222353), and Intermediate 2F by using a similar synthetic protocol as that of Example 14.¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.28 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 5.21 - 5.10 (m, 1H), 4.80 - 4.67 (m, 2H), 4.03 - 3.90 (m, 6H), 3.73 - 3.69 (m, 2H), 3.63 - 3.48 (m, 4H), 3.31 - 3.07 (m, 4H), 1.97 - 1.61 (m, 3H), 1.57 - 1.43 (m, 4H), 1.40 - 1.28 (m, 1H), 1.21 - 0.99 (m, 7H), 0.95 - 0.94 (m, 2H). LCMS (ESI, m/z): 598 [M+H]⁺. LCMS RT: 1.244 min (Method B2). Example 21. (R)-2,5,5-trimethyl-1²-(1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacyclododecaphan-4-one O O O ⁺ _{Br Br} O Br Syn

[0237] To a solution of tert-butyl 2-methylpropanoate (500 mg, 3.47 mmol) in THF (30 mL) at 0 °C under nitrogen was added LDA (2 M in THF, 3.5 mL, 6.93 mmol) dropwise, and the resulting mixture was stirred at 0 °C for 1 h, followed by dropwise addtion of 1,7- dibromoheptane (2.68 g, 10.4 mmol). The resulting mixture was stirred at 0 °C for 0.5 h and at rt for 2 h, then quenched with saturated aqueous NH4Cl (50 mL) at 0 °C, stirred at rt for 20 min, and extracted with ethyl acetate (2*100 mL). The combined organic extract was washed with brine (2*200 mL), dried over anhydrous sodium sulfate, concentrated under vacuum. The crude product was purified by Prep-TLC (petroleum ether / ethyl acetate = 20:1) to afford Intermediate 21A (650 mg) as a light yellow solid. Synthesis of Example 21 [0238] Example 21 was prepared as a white solid from Intermediate 1E, Intermediate 21A, and Intermediate 2F by using a similar synthetic protocol as that of Example 14.¹H NMR (400 MHz, DMSO-d₆+D₂O) δ 8.29 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.11 (s, 1H), 5.17 - 5.08 (m, 1H), 4.82 - 4.49 (m, 2H), 4.01 - 3.95 (m, 6H), 3.80 - 3.77 (m, 1H), 3.71 - 3.67 (m, 1H), 3.66 - 3.48 (m, 4H), 3.37 - 3.28 (m, 3H), 3.22 - 3.02 (m, 1H), 1.83 - 1.64 (m, 2H), 1.58 - 1.30 (m, 5H), 1.28 - 1.16 (m, 6H), 1.15 - 1.03 (m, 2H), 1.02 - 0.88 (m, 6H). LCMS (ESI, m/z): 626 [M+H]⁺. LCMS RT: 1.171 min (Method B3). Example 22. (R)-2-methyl-1²-(1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1¹H-6-oxa-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one

[0239] To a solution of Intermediate 1E (300 mg, 0.86 mmol) in DMF (6 mL) were added ethyl 2-(5-chloropentoxy)acetate (270 mg, 1.29 mmol; Tetrahedron, 2003, 59, 149-153), Cs₂CO₃ (841 mg, 2.58 mmol) and NaI (206 mg, 1.37 mmol). The resulting mixture was stirred at 70 °C overnight, then allowed to cool to rt and directly purified by flash column chromatography on C18 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 10% B to 80% B) to afford Intermediate 22A (240 mg) as a yellow oil. LCMS (ESI, m/z): 520 [M+H]⁺ . Synthesis of Intermediate 22B [0240] To a solution of Intermediate 22A (240 mg, 0.46 mmol) in DCM (5 mL) was added TFA (1 mL). The resulting mixture was stirred at rt for 1 h, then concentrated under vacuum to afford crude Intermediate 22B (190 mg) as a yellow oil. LCMS (ESI, m/z): 420 [M+H]⁺ . Synthesis of Intermediate 22C [0241] To a solution of Intermediate 22B (190 mg, 0.45 mmol) in methanol (2.5 mL) and water (2.5 mL) at rt was added NaOH (108 mg, 2.7 mmol). The resulting mixture was stirred at 50 °C for 1 h under nitrogen, then neutralized with aqueous HCl (4 M) and directly purified by flash column chromatography on C18 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 0% B to 60% B) to afford Intermediate 22C (130 mg) as a yellow oil. LCMS (ESI, m/z): 350 [M+H]⁺ . Synthesis of Intermediate 22D [0242] To a solution of Intermediate 22C (150 mg, 0.43 mmol) in DMF (4 mL), were added HATU (245 mg, 0.64 mmol) and DIPEA (147 mg, 1.29 mmol). The resulting solution was stirred at room temperature for 1 h, then used in the next step directly without further purification. LCMS (ESI, m/z): 450 [M+H]+ . Synthesis of Example 22 [0243] Example 22 was prepared as a white solid from Intermediate 22D and Intermediate 2F by using a similar synthetic protocol as that of Example 2.¹H NMR (400 MHz, DMSO-d₆+D₂O) δ 8.30 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.15 (s, 1H), 5.26 - 5.25 (m, 1H), 4.69-4.66 (m, 2H), 4.20 - 4.16 (m, 1H), 4.03 - 3.90 (m, 6H), 3.75 - 3.69 (m, 4H), 3.66 - 3.44 (m, 5H), 3.31 - 3.20 (m, 3H), 3.09 - 3.07 (m, 1H), 2.17 - 2.06 (m, 1H), 1.81 - 1.75 (m, 2H), 1.65 - 1.61 (m, 2H), 1.48 (d, J = 7.2 Hz, 3H), 1.28 - 1.26 (m, 1H). LCMS (ESI, m/z): 586 [M+H]⁺. LCMS RT: 1.347 min (Method B4). Example 23. (R)-2,5,5-trimethyl-1²-(1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1¹H-6,9-dioxa-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one

Synthesis of Intermediate 23A [0244] To a mixture of tert-butyl 2-bromo-2-methylpropanoate (1 mL, 5.36 mmol) and diethylene glycol (1.018 mL, 10.72 mmol) in DMSO (17.87 mL) was added potassium tert- butoxide (782 mg, 6.97 mmol). The resulting mixture was brought to 60 °C and stirred overnight, then cooled to rt, diluted with EtOAc, washed with water (3X), brine, dried over MgSO4, filtered and concentrated under vacuum to afford crude Intermediate 23A (192 mg) which was used in the next step without further purification. Synthesis of Intermediate 23B [0245] To a mixture of Intermediate 23A (192 mg, 0.773 mmol) and triethylamine (323 µL, 2.320 mmol) in DCM (7.0 mL) at 0 ^oC was added p-toluenesulfonyl chloride (221 mg, 1.160 mmol) and DMAP (9.45 mg, 0.077 mmol). The resulting mixture was stirred at rt for 1 h, then diluted with DCM, washed with water (2X), brine, dried over MgSO₄, filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica (15 to 40% ethyl acetate in hexanes) to afford Intermediate 23B (37 mg).¹H NMR (400 MHz, DMSO-d6) δ 8.90 - 8.89 (m, 1H), 7.79 (br d, J=8.0 Hz, 2H), 7.49 (br d, J=8.1 Hz, 2H), 4.17 - 4.07 (m, 2H), 3.63 - 3.55 (m, 2H), 3.47 - 3.41 (m, 2H), 3.40 - 3.34 (m, 2H), 2.46 - 2.40 (m, 3H), 1.41 (s, 9H), 1.27 (s, 6H). Synthesis of Example 23 [0246] Example 23 was prepared from Intermediate 9C and Intermediate 23B by using a similar synthetic protocol as that of Example 12. LCMS ESI 616 [M+H]⁺. LCMS RT: 1.22 min (Method J).

Example 24. (2R)-2-methyl-1²-(1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1¹H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridina- 5(1,2)-cyclopropanacyclononaphan-4-one

[0247] Tert-butyl 2-(4-((tert-butyldiphenylsilyl)oxy)butyl)cyclopropane-1-carboxylate* was purified by SFC (Column: (R,R) WHELK-O 14.6*50 mm, 3 µm; Mobile Phase B: 1% of 2 M NH₃-MeOH in IPA / hexanes = 1:10; Flow rate: 4 mL/min; Gradient: isocratic B). The pure fractions were concentrated under vacuum to afford a first eluting stereoisomer (280 mg) and Intermediate 24A (300 mg, second eluting stereoisomer) as light yellow oil. Note: the cis/trans composition was not determined. LCMS (ESI, m/z): 453[M+H]⁺. *prepared from 5- hydroxypentanal according to similar synthetic protocols as described in WO2021222353. Synthesis of Intermediate 24B [0248] To a solution of Intermediate 24A (260 mg, 0.57 mmol) in THF (5 mL) at 0 °C was added TBAF (5 mL). The resulting mixture was stirred at rt for 1 h, then diluted with water (30 mL) and extracted with ethyl acetate (30 mL). The organic extract was washed with water (5*30 mL) and brine (5*30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 1:1) to afford Intermediate 24B (110 mg) as a light yellow oil. LCMS (ESI, m/z): 215 [M+H]⁺ . Synthesis of Intermediate 24C [0249] To a solution of Intermediate 24B (85 mg, 0.38 mmol) in DCM (4 mL) at 0 °C under nitrogen were added Et₃N (0.2 mL, 1.12 mmol), DMAP (4 mg, 0.04 mmol) and TsCl (106 mg, 0.56 mmol) in portions. The resulting mixture was stirred at rt overnight, then diluted with water (10 mL) and extracted with DCM (3*10 mL). The combined organic extract was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 5:1) to afford Intermediate 24C (120 mg) as a light yellow oil. LCMS (ESI, m/z): 369 [M+H]⁺ . Synthesis of Intermediate 24D [0250] To a solution of Intermediate 1E (120 mg, 0.35 mmol) in DMF (4 mL) were added Intermediate 24C (120 mg, 0.33 mmol) and Cs₂CO₃ (344 mg, 1.05 mmol). The resulting mixture was stirred at 50 °C overnight, then allowed to cool to rt and directly purified by flash column chromatography on C18 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 10% B to 100% B) to afford Intermediate 24D (110 mg) as a yellow solid. LCMS (ESI, m/z): 544 [M+H]⁺ . Synthesis of Intermediate 24E [0251] A solution of Intermediate 24D (90 mg, 0.16 mmol) in HCl (4 M in EtOAc, 1 mL) under nitrogen was stirred at rt for 3 h. The mixture was concentrated under vacuum and the resulting crude product was purified by flash column chromatography on C18 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 50% B to 100% B) to afford Intermediate 24E (60 mg) as a yellow oil. LCMS (ESI, m/z): 388 [M+H]⁺ . Synthesis of Example 24 [0252] Example 24 was prepared as a light yellow oil from Intermediate 24E and Intermediate 2F by using a similar synthetic protocol as that of Example 14.¹H NMR (400 MHz, DMSO-d₆+D₂O) δ 8.28 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.04 (s, 1H), 5.10 - 5.05 (m, 1H), 4.78 - 4.72 (m, 1H), 4.27 - 4.22 (m, 1H), 4.01 (s, 3H), 3.99 - 3.91 (m, 4H), 3.90 - 3.88 (m, 1H), 3.67 - 3.59 (m, 3H), 3.57 - 3.48 (m, 1H), 3.29 - 3.20 (m, 3H), 3.08 - 3.03 (m, 1H), 2.21 - 2.05 (m, 1H), 1.82 - 1.57 (m, 5H), 1.46 (d, J = 7.2 Hz, 3H), 1.05 - 1.03 (m, 1H), 0.95 - 0.89 (m, 2H), 0.69 - 0.61 (m, 1H). LCMS (ESI, m/z): 582 [M+H]⁺. LCMS RT: 1.316 min (Method B4). Example 25. (R)-2,5,5-trimethyl-1²-(1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1¹H-6-oxa-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one Synthe [025

3] Example 25 was prepared from Intermediate 9C and tert-butyl 2-methyl-2-((5- (tosyloxy)pentyl)oxy)propanoate* by using a similar synthetic protocol as that of Example 12. LCMS (ESI, m/z): 614 [M+H]⁺. LCMS RT: 1.46 min (Method J). *prepared according to similar synthetic protocols as described in WO2021222353. Example 26 & Example 27. (2R)-5-fluoro-2-methyl-1²-(1-methyl-6-(((S)-morpholin-3- yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-5-(pyridin-2-yl)- 1¹H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecaphan-4-one

[0254] Intermediate 26A was prepared from tert-butyl 2-(pyridin-2-yl)acetate and ((6- bromohexyl)oxy)(tert-butyl)dimethylsilane according to similar synthetic protocols as described in WO2021222353 for 6-((tert-butyldimethylsilyl)oxy)hexyl trifluoromethanesulfonate. LCMS (ESI, m/z): 466 [M+H]⁺ . Synthesis of Example 26 & Example 27 [0255] A mixture of Example 26 and Example 27 was prepared from Intermediate 9C and Intermediate 26A by using a similar synthetic protocol as that of Example 12. The mixture was separated by Prep-HPLC (Method I2) to afford two homochiral, diastereomeric products. Example 26 (diastereomer 1, first eluting): ¹H NMR (500 MHz, DMSO-d6) δ 8.76 - 8.68 (m, 1H), 8.65 - 8.55 (m, 1H), 8.28 (s, 1H), 8.13 - 8.05 (m, 1H), 7.99 - 7.94 (m, 1H), 7.93 - 7.86 (m, 1H), 7.65 - 7.57 (m, 2H), 7.47 - 7.39 (m, 1H), 7.27 - 7.22 (m, 1H), 7.19 - 7.13 (m, 1H), 5.35 - 5.22 (m, 1H), 5.01 - 4.88 (m, 1H), 4.80 - 4.67 (m, 1H), 3.98 (s, 3H), 3.96 - 3.78 (m, 2H), 3.74 - 3.61 (m, 2H), 3.57 - 3.48 (m, 1H), 3.29 - 3.12 (m, 2H), 3.07 - 2.96 (m, 1H), 2.90 (s, 3H), 2.74 (s, 3H), 2.22 - 1.95 (m, 2H), 1.78 - 1.63 (m, 1H), 1.56 (br d, J = 7.1 Hz, 4H), 1.44 - 1.33 (m, 1H), 1.33 - 1.23 (m, 2H), 1.18 - 1.03 (m, 1H), 0.87 - 0.71 (m, 1H). LCMS (ESI, m/z): 679 [M+H]⁺. LCMS RT: 1.27 min (Method J). [0256] Example 27 (diastereomer 2, second eluting): ¹H NMR (500 MHz, DMSO-d6) δ 8.69 - 8.62 (m, 1H), 8.35 - 8.30 (m, 1H), 8.29 - 8.24 (m, 1H), 8.11 - 8.06 (m, 1H), 7.98 - 7.95 (m, 1H), 7.94 - 7.89 (m, 1H), 7.63 - 7.56 (m, 2H), 7.48 - 7.41 (m, 1H), 7.24 - 7.18 (m, 1H), 7.16 - 7.11 (m, 1H), 5.13 - 5.02 (m, 1H), 4.94 - 4.81 (m, 1H), 4.65 - 4.49 (m, 1H), 3.98 (s, 3H), 3.95 - 3.78 (m, 2H), 3.74 - 3.58 (m, 2H), 3.56 - 3.45 (m, 1H), 3.25 - 3.14 (m, 2H), 3.04 - 2.94 (m, 1H), 2.93 - 2.87 (m, 3H), 2.76 - 2.71 (m, 3H), 2.19 - 1.96 (m, 2H), 1.85 - 1.63 (m, 2H), 1.56 - 1.37 (m, 6H), 1.32 - 1.21 (m, 2H). LCMS (ESI, m/z): 340 [M+2H]⁺. LCMS RT: 1.28 min (Method J).

Example 28. (R)-2,5,5-trimethyl-1²-(1-methyl-5-oxo-6-(((S)-pyrrolidin-2-yl)methyl)-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one

y [0257] To solid 6-fluoro-3,4-dihydroisoquinolin-1(2H)-one (15.0 g, 90.8 mmol) was added H2SO4 (200 mL) dropwise at 0 °C, followed by portionwise addition of KNO3 (36.7 g, 364 mmol). The resulting mixture was stirred at rt for 3 h, then added dropwise into ice-water (1 L) and extracted with ethyl acetate (2*1 L). The combined organic extract was washed with brine (2 L), dried over anhydrous sodium sulfate, and concentrated under vacuum to afford crude Intermediate 28A (22.5 g) as a yellow solid. LCMS (ESI, m/z): 211 [M+H]⁺ . Synthesis of Intermediate 28B [0258] To a solution of Intermediate 28A (20.0 g, 94.8 mmol) in MeCN (200 mL) at rt were added methylamine-hydrochloride (12.8 g, 190 mmol) and DIPEA (36.8, 285 mmol). The resulting mixture was stirred at rt for 2 h, then diluted with water (1 L) and extracted with DCM (2*1 L). The combined organic extract was washed with water (2 L) and brine (2 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (100% ethyl acetate) to afford Intermediate 28B (15 g) as a yellow solid. LCMS (ESI, m/z): 222 [M+H]⁺ .

Synthesis of Intermediate 28C

[0259] To a solution of Intermediate 28B (10 g, 45 mmol) in methanol (210 mb) was added saturated aqueous NH4CI (70 mL), followed by portionwise addition of zinc powder (29.3 g, 450 mmol), and the resulting mixture was stirred at rt for 2 h. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was diluted with water (500 mL) and extracted with DCM (2*500 mL). The combined organic extract was washed with water (1 L) and brine (1 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (DCM / MeOH = 10: 1) to afford Intermediate 28C (4.6 g) as a grey solid. LCMS (ESI, m/z): 192 [M+H]⁺ .

Synthesis of Intermediate 28D

[0260] To a solution of Intermediate II (3.5 g, 9.7 mmol) and DIPEA (3.82 g, 28.6 mmol) in DMF (100 mL) at rt under nitrogen was added HATU (4.8 g, 12.7 mmol). The mixture was stirred at rt for 10 min, then added dropwise into a solution of Intermediate 28C (2.8 g, 14.6 mmol) in DMF (10 mL) at rt. The resulting mixture was stirred at rt for 3 h, then diluted with water (500 mL) and extracted with ethyl acetate (500 mL). The combined organic extract was washed with water (2*500 mL) and brine (2*500 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on C18 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 0% B to 100% B) to afford Intermediate 28D (4.6 g) as a yellow solid. LCMS (ESI, m/z): 531 [M+H]⁺ .

Synthesis of Intermediate 28E

[0261] A solution of Intermediate 28D (1.3 g, 2.5 mmol) in acetic acid (25 mL) was stirred at 70 °C for 3 h, then concentrated under vacuum. The crude product was purified by flash column chromatography on C18 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 0% B to 100% B) to afford Intermediate 28E (1.06 g) as a yellow solid. LCMS (ESI, m/z): 513 [M+H]⁺ . Synthesis of Intermediate 28F [0262] To a solution of Intermediate 28E (50 mg, 0.10 mmol) in THF (3 mL) at 0 °C under nitrogen was added NaH (60% w/w, 16 mg, 0.67 mmol) in portions, and the resulting mixture was stirred at rt for 0.5 h. The reaction mixture was cooled to 0 °C, and (S)-tetrahydro- 3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (32 mg, 0.20 mmol) was added in portions. The resulting mixture was stirred at rt overnight, then quenced with saturated aqueous NH₄Cl (0.5 mL), and directly purified by flash column chromatography on C18 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 0% B to 100% B) to afford Intermediate 28F (40 mg) as a yellow solid. LCMS (ESI, m/z): 676 [M+H]⁺ . Synthesis of Example 28 [0263] A solution of Intermediate 28F (25 mg, 0.04 mmol) in HCl (4 M in MeOH, 2 mL) was stirred at 70 °C overnight in a sealed vessel, then concentrated under vacuum. The crude product was purified by Prep-HPLC (Method E4, RT: 8.5 min). The pure fractions were concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to afford Example 28 (15.6 mg) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 9.03 (s, br 1H), 8.40 (s, br 1H), 8.26 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.62 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 5.14 - 5.12 (m, 1H), 4.93 - 4.80 (m, 1H), 4.61 - 4.52 (m, 1H), 3.96 (s, 3H), 3.94 - 3.89 (m, 2H), 3.75 - 3.72 (m, 2H), 3.37 - 3.22 (m, 2H), 3.21 - 3.13 (m, 3H), 2.17 - 2.06 (m, 1H), 1.97 - 1.90 (m, 3H), 1.75 - 1.65 (m, 3H), 1.52 - 1.41 (m, 4H), 1.38 - 1.38 (m, 4H), 1.21 (s, 3H), 1.17 - 1.07 (m, 2H), 0.94 (s, 3H). LCMS (ESI, m/z): 596 [M+H]⁺. LCMS RT: 0.697 min (Method B1). Example 29. (R)-2,5,5-trimethyl-12-(1-methyl-5-oxo-6-(((R)-pyrrolidin-2-yl)methyl)-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-11H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one

Synthesis of Example 29 [0264] Example 29 was prepared as a white solid from Intermediate 28E and (R)- tetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide by using a similar synthetic protocol as that of Example 28.¹H NMR (400 MHz, DMSO-d6) δ 9.04 (s, br, 1H), 8.41 (s, br, 1H), 8.26 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 5.16 - 5.08 (m, 1H), 4.89 - 4.83 (m, 1H), 4.60 - 4.52 (m, 1H), 3.97 (s, 3H), 3.95 - 3.89 (m, 1H), 3.82 - 3.76 (m, 1H), 3.74 - 3.64 (m, 3H), 3.37 - 3.28 (m, 1H), 3.21 - 3.11 (m, 3H), 2.12 - 2.07 (m, 1H), 2.01 - 1.88 (m, 3H), 1.74 - 1.55 (m, 3H), 1.45 (d, J = 8.0 Hz, 3H), 1.41 - 1.33 (m, 5H), 1.21 (s, 3H), 1.11 - 1.05 (m, 2H), 0.94 (s, 3H). LCMS (ESI, m/z): 596 [M+H]⁺. LCMS RT: 0.693 min (Method B1). Example 30. (R)-1²-(6-(((R)-4,4-difluoropiperidin-2-yl)methyl)-1-methyl-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-2,5,5-trimethyl-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one

[0265] To a solution of (R)-1-(tert-butoxycarbonyl)-4,4-difluoropiperidine-2-carboxylic acid (500 mg, 1.89 mmol) in THF (20 mL) at 0 °C under nitrogen was added BH3 (1M in THF, 3.8 mL, 3.8 mmol). The resulting mixture was stirred at rt overnight, then added into methanol at 0 °C, stirred at 0 °C for 20 min and concentrated under vacuum. The crude product was purified by Prep-TLC (petroleum ether / ethyl acetate = 2:1) to afford Intermediate 30A (300 mg) as a white solid. LCMS (ESI, m/z): 252 [M+H]⁺ . Synthesis of Intermediate 30B

[0266] To a solution of Intermediate 30A (150 mg, 0.6 mmol) in ethyl acetate (1 mL) at rt was added HC1 (4 M in EtOAc, 4 mL, 16 mmol). The resulting mixture was stirred at rt for 1 h, then concentrated under vacuum to afford Intermediate 30B (80 mg) as a white solid. LCMS (ESI, m/z): 152 [M+H]⁺ .

Synthesis of Intermediate 30C

[0267] To a solution of imidazole (216 mg, 3.18 mmol) in DCM (2 mL) at 0 °C under nitrogen was added a solution of SOCh (108 mg, 0.95 mmol) in DCM (2 mL) dropwise. The resulting mixture was stirred at rt for 1 h, then cooled to -10 °C, and a solution of Intermediate 30B (80 mg, 0.53 mmol) in DCM (2 mL) was added dropwise under nitrogen. The resulting mixture was stirred at rt for 1 h, then diluted with water (10 mL), acidified to pH 6 with citric acid, and extracted with DCM (3*10 mL). The combined organic extract was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford Intermediate 30C (80 mg) as a white solid. LCMS (ESI, m/z): 198 [M+H]⁺ .

Synthesis of Intermediate 30D

[0268] To a solution of Intermediate 30C (80 mg, 0.41 mmol) in MeCN (2 mL) at rt was added a solution of NaICU (88 mg, 0.41 mmol) and RuCh (10.3 mg, 0.04 mmol) in H2O (1 mL). The resulting mixture was stirred at rt for 2 h, then diluted with water (10 mL) and extracted with DCM (3*10 mL). The combined organic extract was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to afford Intermediate 30D (80 mg) as a white solid. LCMS (ESI, m/z): 214 [M+H]⁺ .

Synthesis of Intermediate 30E

[0269] To a solution of Intermediate 28E (50 mg, 0.10 mmol) in THF (2 mL) at 0 °C under nitrogen was added NaH (60% w/w, 7.0 mg, 0.20 mmol), and the resulting mixture was stirred at rt for 0.5 h. The reaction mixture was cooled to 0 °C, and a solution of Intermediate 30D (103 mg, 0.49 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at 50 °C overnight, then quenched with saturated aqueous NH4CI (0.5 mL) and directly purified by flash column chromatography on C18 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 5% B to 80% B) to afford Intermediate 30E (60 mg) as a white solid. LCMS (ESI, m/z): 726 [M+H]⁺ . Synthesis of Example 30 [0270] A solution of Intermediate 30E (60 mg, 0.08 mmol) in HCl (4 M in MeOH, 4 mL) was stirred at 50 °C for 2 h in a sealed vessel, then concentrated under vacuum. The crude product was purified by Prep-HPLC (Method E3, RT: 8.68 min). The pure fractions were concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to afford Example 30 (53.4 mg) as a white solid.¹H NMR (400 MHz, DMSO- d6+D2O) δ 8.27 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.07 (s, 1H), 5.08 - 5.07 (m, 1H), 4.83 - 4.80 (m, 1H), 4.42 - 4.40 (m, 1H), 4.01 (s, 3H), 3.72 - 3.51 (m, 5H), 3.53 - 3.48 (m, 1H), 3.23 - 3.19 (m, 2H), 3.01 - 2.98 (m, 1H), 2.51 - 2.33 (m, 4H), 1.90 - 1.80 (m, 1H), 1.69 - 1.58 (m, 2H), 1.43 (d, J = 6.8 Hz, 3H), 1.40 - 1.35 (m, 2H), 1.24 - 1.20 (m, 3H), 1.18 (s, 3H), 1.10 - 1.00 (m, 2H), 0.92 (s, 3H). LCMS (ESI, m/z): 646 [M+H]⁺. LCMS RT: 0.725 min (Method B1). [0271] Examples 31-38 (see Table 1) were prepared from Intermediate 28E and appropriate commercially available precursors by using a similar synthetic protocol as that of Example 30. Table 1. Characterization of Examples 31-38. Example LCMS m/z [M+H]⁺; LCMS RT (LCMS method); ¹H Structure - n , , = 4 , 6

(m 4H) 215 190 (m 4H) 170 157 (m 2H) 145

(R)-2,5,5-trimethyl-1²-(1-methyl-5-oxo-6-(((R)-

1.54 (m, 8H), 1.21 (s, 3H), 1.14 - 1.02 (m, 2H), 0.94 (s,

3H), 1.50 - 1.39 (m, 5H), 1.31 (s, 3H), 1.29 - 1.13 (m,

2H), 1.59 - 1.34 (m, 9H), 1.21 (s, 3H), 1.15 - 1.01 (m,

tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one

[0272] To a solution of tert-butyl (S)-2-(hydroxymethyl)morpholine-4-carboxylate (500 mg, 2.3 mmol) in DCM (23 mL) at 0 °C under nitrogen were added Ms2O (905 mg, 3.4 mmol) and Et₃N (465 mg, 4.6 mmol). The resulting mixture was stirred at rt for 2 h under nitrogen, then diluted with saturated aqueous NH4Cl (20 mL) at 0 °C and extracted with DCM (2*20 mL). The combined organic extract was washed with brine (2*20 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by Prep-TLC (petroleum ether / ethyl acetate = 5:1) to afford Intermediate 39A (400 mg) as a light yellow oil. LCMS (ESI, m/z): 296 [M+H]⁺ . Synthesis of Intermediate 39B [0273] To a solution of Intermediate 28E (60 mg, 0.12 mmol) in DMF (3 mL) at 0 °C under nitrogen was added NaH (60% w/w, 14 mg, 0.35 mmol) in portions, and the resulting mixture was stirred at rt for 0.5 h. The reaction was cooled to 0 °C, and a solution of Intermediate 39A (34 mg, 0.12 mmol) in DMF (0.5 mL) was added dropwise. The resulting mixture was stirred at 50 °C for 2 h, then quenched with saturated aqueous NH4Cl (0.5 mL) and directly purified by flash column chromatography on C18 silica (Mobile Phase A: 0.5% TFA in water, Mobile Phase B: ACN; Gradient: 0% B to 100% B) to afford Intermediate 39B (29 mg) as a yellow solid. LCMS (ESI, m/z): 712 [M+H]⁺ . Synthesis of Example 39 [0274] To a solution of Intermediate 39B (30 mg, 0.04 mmol) in DCM (3 mL) was added TFA (1 mL). The resulting mixture was stirred at rt for 1 h, then concentrated under vacuum. The crude product was purified by Prep-HPLC (Method E5, RT: 8.5 min). The pure fractions were concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to afford Example 39 (15.6 mg) as a white solid.¹H NMR (400 MHz, DMSO- d₆+D₂O) δ 8.26 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.31 - 7.06 (m, 3H), 5.14 - 5.10 (m, 1H), 5.09 - 4.86 (m, 1H), 4.59 - 4.39 (m, 1H), 3.99 - 3.95 (m, 5H), 3.79 - 3.62 (m, 5H), 3.29 (d, J = 12 Hz, 1H), 3.28 - 3.17 (m, 3H), 3.06 - 3.01 (m, 1H), 2.95 - 2.87 (m, 1H), 1.97 - 1.89 (m, 1H), 1.79 - 1.59 (m, 1H), 1.43 (d, J = 8.0 Hz, 3H), 1.41 - 1.18 (m, 6H), 1.17 (s, 3H), 1.15 - 0.90 (m, 2H), 0.89 (s, 3H). LCMS (ESI, m/z): 612 [M+H]⁺. LCMS RT: 0.681 min (Method B1). Example 40. (R)-2,5,5-trimethyl-1²-(1-methyl-5-oxo-6-((R)-pyrrolidin-3-yl)-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one S

[0275] To a solution of tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (300 mg, 1.60 mmol) in DCM (16 mL) at 0 °C under nitrogen were added Et₃N (0.84 mL, 4.81 mmol) and MsCl (219 mg, 1.92 mmol). The resulting mixture was stirred at rt for 1 h, then quenched with saturated aqueous NH4Cl (20 mL) at 0 °C and extracted with DCM (2*20 mL). The combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum at 0 °C to afford Intermediate 40A (300 mg) as a light yellow oil. LCMS (ESI, m/z): 266 [M+H]⁺ . Synthesis of Example 40 [0276] Example 40 was prepared as a white solid from Intermediate 28E and Intermediate 40A by using a similar synthetic protocol as that of Example 39.¹H NMR (400 MHz, DMSO-d₆) δ 8.90 - 8.82 (m, 2H), 8.24 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.2 Hz, 1H), 7.61 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 5.18 - 5.02 (m, 2H), 4.85 - 4.83 (m, 1H), 4.55 - 4.52 (m, 1H), 3.96 (s, 3H), 3.63 - 3.60 (m, 2H), 3.23 - 3.16 (m, 6H), 2.29 - 2.18 (m, 1H), 2.18 - 2.07 (m, 1H), 2.04 - 1.96 (m, 1H), 1.69 - 1.60 (m, 2H), 1.45 (d, J = 8.0 Hz, 3H), 1.46 - 1.34 (m, 5H), 1.21 (s, 3H), 1.09 - 1.07 (m, 2H), 0.95 (s, 3H). LCMS (ESI, m/z): 582 [M+H]⁺. LCMS RT: 0.678 min (Method B1). Example 41. (R)-1²-(6-((S)-2-amino-3-methoxypropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro- 1H-imidazo[4,5-g]isoquinolin-2-yl)-2,5,5-trimethyl-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one S

y [0277] To a solution of N-(tert-butoxycarbonyl)-O-methyl-D-serine (2 g, 9.12 mmol) in THF (90 mL) at 0 °C was added BH3 (1 M in THF, 18 mL, 18 mmol). The resulting mixture was stirred at rt for 6 h, then quenched with methanol (0.6 mL) at 0 °C and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 3:1) to afford Intermediate 41A (1 g) as a white solid. LCMS (ESI, m/z): 206 [M+H]⁺ . Synthesis of Intermediate 41B [0278] To a solution of imidazole (1.19 g, 17.54 mmol) in DCM (5 mL) at 0 °C was added SOCl₂ (626 mg, 5.26 mmol) in DCM (5 mL) dropwise. The resulting mixture was stirred at rt for 1 h, then cooled to -10 °C, and a solution of Intermediate 41A (600 mg, 2.92 mmol) in DCM (5 mL) was added. The resulting mixture was stirred at rt for 2 h, then diluted with water (50 mL) and extracted with DCM (3*50 mL). The combined organic extract was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 4:1) to afford Intermediate 41B (300 mg) as a white solid. LCMS (ESI, m/z): 252[M+H]⁺ . Synthesis of Intermediate 41C [0279] To a solution of Intermediate 41B (300 mg, 1.19 mmol) in acetonitrile (8 mL) at rt was added a solution of NaIO₄ (255 mg, 1.19 mmol) and RuCl₃ (24 mg, 0.12 mmol) in water (4 mL). The resulting mixture was stirred at rt for 1 h, then concentrated under vacuum. The residue was diluted with water (30 mL) and extracted with DCM (3*30 mL). The combined organic extract was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 4:1) to afford Intermediate 41C (200 mg) as a white solid. LCMS (ESI, m/z): 268 [M+H]⁺ . Synthesis of Intermediate 41D [0280] To a solution of Intermediate 28E (100 mg, 0.20 mmol) in DMF (2 mL) at 0 °C under nitrogen was added NaH (60% w/w, 15 mg, 0.39 mmol) in portions. The resulting mixture was stirred at rt for 0.5 h, then cooled to 0 °C and Intermediate 41C (62 mg, 0.23 mmol) was added. The resulting mixture was stirred at rt for 4 h, then quenched with water (10 mL) and extracted with ethyl acetate (3*10 mL). The combined organic extract was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 1:2) to afford Intermediate 41D (90 mg) as a colorless oil. LCMS (ESI, m/z): 700 [M+H]⁺ . Synthesis of Example 41 [0281] To a solution of Intermediate 41D (35 mg, 0.05 mmol) in DCM (2 mL) was added TFA (0.5 mL). The resulting mixture was stirred at rt for 1 h, then concentrated under vacuum. The crude product was purified by Prep-HPLC (Method E5, RT: 8.5 min). The pure fractions were concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to afford Example 41 (13.5 mg) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.06 - 8.04 (m, 4H), 7.83 (d, J = 8.0 Hz, 1H), 7.59 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 5.13 - 5.11 (m, 1H), 4.88 - 4.85 (m, 1H), 4.55 (s, br, 1H), 3.96 (s, 3H), 3.82 - 3.80 (m, 1H), 3.78 - 3.75 (m, 4H), 3.64 - 3.57 (m, 3H), 3.55 - 3.52 (m, 2H), 3.38 - 3.36 (m, 2H), 1.96 - 1.92 (m, 1H) 1.78 - 1.59 (m, 2H), 1.57 - 1.52 (m, 4H), 1.51 - 1.46 (m, 4H), 1.35 (s, 3H), 1.30 - 1.22 (s, 2H), 0.91 (s, 3H). LCMS (ESI, m/z): 600 [M+H]⁺. LCMS RT: 1.386 min (Method B5). Example 42. (R)-1²-(6-((S)-3-methoxy-2-(methylamino)propyl)-1-methyl-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-2,5,5-trimethyl-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one

g under nitrogen was added NaH (60% w/w, 4 mg, 0.20 mmol) in portions. The resulting mixture was stirred at rt for 0.5 h, then cooled to 0 °C and MeI (28.4 mg, 0.20 mmol) was added dropwise. The resulting mixture was stirred at rt for 2 h, then quenched with water (10 mL) and extracted with ethyl acetate (3*10 mL). The combined organic extract was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (petroleum ether / ethyl acetate = 1:2) to afford Intermediate 42A (35 mg) as a colorless oil. LCMS (ESI, m/z): 714 [M+H]⁺ . Synthesis of Example 42 [0283] To a solution of Intermediate 42A (35 mg, 0.04 mmol) in DCM (2 mL) was added TFA (0.5 mL). The resulting mixture was stirred at rt for 1 h, then concentrated under vacuum. The crude product was purified by Prep-HPLC (Method G, RT: 8.57 min). The pure fractions were concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to afford Example 42 (20.5 mg) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (s, br, 2H), 8.24 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.60 (s, 1H), 7.23 - 7.18 (m, 1H) 7.10 (s, 1H), 5.13 - 5.10 (m, 1H), 4.89 - 4.85 (m, 1H), 4.55 (s, br, 1H), 3.96 (s, 3H), 3.92 - 3.88 (m, 1H), 3.68 - 3.60 (m, 6H), 3.44 (s, 3H), 3.22 - 3.17 (m, 2H), 2.67 - 2.49 (m, 3H), 1.97 - 1.93 (m, 1H), 1.67 - 1.58 (m, 2H), 1.46 - 1.44 (m, 4H), 1.39 - 1.33 (m, 4H), 1.20 (s, 3H), 1.09 - 1.06 (m, 2H) 0.94 (s, 3H). LCMS (ESI, m/z): 614 [M+H]⁺. LCMS RT: 1.418 min (Method B5). Example 43. (R)-1²-(6-(((S)-4,4-difluoropyrrolidin-2-yl)methyl)-1-methyl-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-2,5,5-trimethyl-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one

[0284] To a solution of tert-butyl (S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1- carboxylate (150 mg, 0.632 mmol), DMAP (7.72 mg, 0.063 mmol) and Et3N (0.220 mL, 1.581 mmol) in DCM (5 mL) at 0 °C was added a premade solution of 4-methylbenzenesulfonyl chloride (133 mg, 0.695 mmol) in DCM (2 mL) dropwise. The resulting mixture was stirred at rt overnight, then diluted with water and extracted with DCM. The organic extract was washed with saturated aqueous NaHCO₃ and brine, dried over magnesium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography on silica (0 to 20% ethyl acetate in hexanes) to afford Intermediate 43A as a colorless oil. LCMS (ESI, m/z): 291.8 [M+H-Boc]⁺ . Synthesis of Example 43 [0285] Example 43 was prepared from Intermediate 28E and Intermediate 43A by using a similar synthetic protocol as that of Example 39. LCMS (ESI, m/z): 632 [M+H]⁺. LCMS RT: 1.53 min (Method J). Example 44. (R)-1²-(6-(((R)-4,4-difluoropyrrolidin-2-yl)methyl)-1-methyl-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-2,5,5-trimethyl-1¹H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one Synthesis of Ex [0286] E

xample 44 was prepared from Intermediate 28E (80 mg, 0.156 mmol) and tert- butyl (R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate by using a similar synthetic protocol as that of Example 43. LCMS (ESI, m/z): 632 [M+H]⁺. LCMS RT: 1.5 min (Method J). RFMS Assay [0287] Compounds were solubilized in 100% DMSO to achieve a 10 mM concentration. Compound stock solutions were stored at rt. A series of dilutions were prepared in DMSO and mixed 8 times with 20 µL mixing volume. Final top concentration of compound in the assay is 15 μM. Final assay conditions were as follows: Reaction volume: 26 µL; Assay buffer: 25 mM HEPES pH 7.5, 5 mM NaCl, 1 mM DTT, 0.2 mg/mL BSA, 0.01% CHAPS, 5 µM TPEN, and 50 µM Calcium (Condition 1) or 1 mM Calcium (Condition 2); Final concentrations: 5 nM hPAD4 enzyme, 250 µM BAEE, and 0.5% DMSO; Total incubation time: 30 min compound and enzyme preincubation at 37 °C, 90 min enzyme/substrate reaction, 30 min reaction with phenyl glyoxal at 37 °C; Stop solution: 40 µL of 5% trichloroacetic acid solution in ACN. [0288] Assay protocol: Compound solution (0.13 µL) was added to a solution of 10 nM PAD4 in assay buffer (13 µL). After 30 min, a solution of 500 µM of BAEE in assay buffer (13 µL) was added and the reaction was incubated for 90 min at 37 °C. The enzymatic reaction was quenched by addition of 6.1 N trichloroacetic acid (15 µL, 100% w/v). Final Concentration: 20%. A solution of 8.5 mM phenyl glyoxal (35 µL) was then added to a final concentration of 4 mM and the reaction was incubated for 30 min at 37 °C. After 30 min, the plates are spun down to remove all precipitate. The enzyme reaction was quenched with an equal volume of methanol containing internal standard (modified citrulline). Samples were loaded onto the Rapid Fire RF300 system (Agilent) wherein they were first sipped for 1000 ms and then directly loaded to a C18 separations cartridge using a mixture of acetonitrile containing 0.01% formic acid for 3000 ms desalting. The flow rate of the mobile phase was 1.5 mL/min. Once the samples were eluted from the cartridge, a mobile phase of acetonitrile containing 0.01% formic acid was used to move the samples into the mass spectrometer for 4000 ms at a flow rate of 1.25 mL/min. Sciex API5500 triple quadrupole mass spectrometer (Applied Biosystems) equipped with ESI was used to analyze the peptidyl citrulline and internal standard ions. [0289] Multiple reaction monitoring transition of product and internal standard were monitored at m/z 424.5 to 350.4 and m/z 293 to 247 respectively. The dwell time for each transition was set at 200 ms, and the ESI voltage was used at 5500 with a source temperature of 400 °C. Extracted ion peaks for each transition were integrated using the Rapid Fire Integrator software. Peak area of analyte was normalized with internal standard. For a given compound example, the Table below shows the human PAD4 (hPAD4) IC₅₀ in the RapidFire mass spectrometry (RFMS) assay. [0290] Table 2, below, shows the activity of selected compounds of this invention in the PAD4 assays described above. Compounds having an activity designated as “A” provided an IC₅₀ ≤ 10nM; compounds having an activity designated as “B” provided an IC5011-100nM; compounds having an activity designated as “C” provided an IC50101-500nM; compounds having an activity designated as “D” provided an IC₅₀501-1000nM; compounds having an activity designated as “E” provided an IC₅₀ > 1000nM. Table 2. Biological Activity Data RFMS Condition 1 (50 µM Ca²⁺) RFMS Condition 2 (1 mM Ca²⁺) Example #

6 C E 7 E E

ENUMERATED EMBODIMENTS Enumerated Embodiment 1. A compound of Formula I: drug, or tautomer thereof,

wherein: X₁ and X₂ are each independently CR₈ or N; Y is selected from -(CR9R10)p–, –O–(CR9R10)p-, –(CR9R10)p–O–(CH2)m-, –(CR9R10)p–O–(CH2)m– O–CH₂–, and –(CR₉R₁₀)_p–O–(CH₂)_m–O–; R₁ is independently –CH(NHR₇)-(C₁-C₃alkyl) or a 4- to 8-membered heterocycle containing at least one heteroatom selected from the group consisting of N, O, or S, wherein the alkyl or heterocycle is optionally substituted with one or more R11; R₂ is independently H, or C₁-C₄ alkyl; R3 is independently H, halogen, or C1-C4 alkyl; R4 is independently hydrogen, C1–C4 alkyl, or C1–C4 haloalkyl; R₅ and R₆ are independently selected from H, halogen, C₁–C₄ alkyl, C₁–C₄ alkoxy, C₁–C₄ haloalkyl, heteroaryl, and aryl; wherein the heteroaryl, or aryl is optionally substituted with one or more halogen or C1–C6 alkoxy; or R₅ and R₆ together with the intervening atoms, form a C₃-C₆ cycloalkyl or 4- to 8-membered heterocyclyl; or R5, R6, and R9 together with the intervening and adjacent atoms, form a C3-C6 cycloalkyl, 4- to 8- membered heterocyclyl, a heteroaryl, or an aryl, wherein the cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more R₁₂; each R7 is independently selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl; each R8 is independently selected from H, halogen, C1–C4 alkyl, C1–C4 haloalkyl, and C1–C4 alkoxy; each R₉ is independently H, halogen, C₁-C₄ alkyl, or C₃-C₄ carbocyclyl; each R10 is independently H, halogen, or C1-C4 alkyl; each R11 is independently selected from H, halogen, C1–C6 alkyl, and C1–C6 alkoxy; each R₁₂ is independently selected from H, halogen, -OH, -NH₂, -CN, C₁–C₆ alkyl, C₁–C₄ alkoxy, C1–C4 haloalkoxy, C1–C4 haloalkyl, and C3–C4 cycloalkyl, 3- to 10-membered heterocyclyl, heteroaryl, and C6–C10 aryl; L is a bond or –CH₂–; m is an integer selected from 1, 2, and 3; and p is an integer selected from 2, 3, 4, 5, and 6. Enumerated Embodiment 2. The compound of Enumerated Embodiment 1, wherein the compound is of Formula (Ia):

w o 3. Enumerated Embodiment 3. The compound of any one of the previous Enumerated Embodiments, wherein the compound is of Formula (Ia-1):

Enumerated Embodiment 4. The compound of Enumerated Embodiment 1 or 2, wherein the compound is of Formula (Ia-2): wherei

n A y y, y, y; wherein X3 is NH, O, or S. Enumerated Embodiment 5. The compound of Enumerated Embodiments 1-3, wherein the compound is of Formula (Ia-3)

Enumerated Embodiment 6. The compound of Enumerated Embodiments 1, 2, or 4, wherein the compound is of Formula (Ia-4)

wherein X₃ is CH₂, NH, O, or S. Enumerated Embodiment 7. The compound of Enumerated Embodiment 1 or 2, wherein the compound is of Formula (Ia-5)

Enumerated Embodiment 8. The compound of Enumerated Embodiment 1, wherein the compound is of Formula (Ib):

f Enumerated Embodiment 1 or 8, wherein the compound is of Formula (Ib-1):

(Ib-1). Enumerated Embodiment 10. The compound of Enumerated Embodiment 1 or 8, wherein the compound is of Formula (Ib-2): (Ib-2) wherein A is C₃-C₈ cycloalkyl, aryl, or heteroaryl. Enumerated Embodiment 11. The compound of Enumerated Embodiment 1 or 8, wherein the compound is of Formula (Ib-3)

(Ib-3). Enumerated Embodiment 12. The compound of Enumerated Embodiment 1 or 8, wherein the compound is of Formula (Ib-4) (Ib-4), wherein A is C3-C8 cycloalkyl, aryl or heteroaryl. Enumerated Embodiment 13. The compound of Enumerated Embodiment 1 or 8, wherein the compound is of Formula (Ib-5)

(Ib-5). Enumerated Embodiment 14. The compound of Enumerated Embodiment 1 or 8, wherein the compound is of Formula (Ib-6) (Ib-6). Enumerated Embodiment 15. The compound of Enumerated Embodiment 1 or 2, wherein the compound is of Formula (Ic):

(Ic). Enumerated Embodiment 16. The compound of Enumerated Embodiment 1 or 15, wherein the compound is of Formula (Ic-1): (Ic-1). Enumerated Embodiment 17. The compound of Enumerated Embodiment 1 or 15, wherein the compound is of Formula (Ic-2):

(Ic-2) wherein A is C3-C8 cycloalkyl, aryl, or heteroaryl. Enumerated Embodiment 18. The compound of Enumerated Embodiment 1 or 15, wherein the compound is of Formula (Ic-3) (Ic-3). Enumerated Embodiment 19. The compound of Enumerated Embodiment 1 or 15, wherein the compound is of Formula (Ic-4)

(Ic-4), wherein A is C₃-C₈ cycloalkyl, aryl, or heteroaryl. Enumerated Embodiment 20. The compound of Enumerated Embodiment 1 or 15, wherein the compound is of Formula (Ic-5): (Ic-5). Enumerated Embodiment 21. The compound of Enumerated Embodiment 1, wherein the compound is of Formula (Id):

(Id), wherein r is an integer from 0 to 2. Enumerated Embodiment 22. The compound of Enumerated Embodiment 1, wherein the compound is of Formula (Ie): (Ie), wherein r is an integer from 0 to 2. Enumerated Embodiment 23. The compound of Enumerated Embodiment 1, wherein the compound is of Formula (If):

(If), wherein A is C₃-C₈ cycloalkyl, aryl, or heteroaryl; and r is an integer from 0 to 2. Enumerated Embodiment 24. The compound of any one of the previous Enumerated Embodiments, wherein R2 is H or C1–C4 alkyl. Enumerated Embodiment 25. The compound of any one of the previous Enumerated Embodiments, wherein R₂ is methyl. Enumerated Embodiment 26. The compound of any one of the previous Enumerated Embodiments, wherein R₃ is H. Enumerated Embodiment 27. The compound of any one of the previous Enumerated Embodiments, wherein R4 is C1–C4 alkyl. Enumerated Embodiment 28. The compound of any one of the previous Enumerated Embodiments, wherein R₄ is methyl. Enumerated Embodiment 29. The compound of any one of the previous Enumerated Embodiments, wherein R7 is methyl. Enumerated Embodiment 30. The compound of any one of the previous Enumerated Embodiments, wherein R7 is cycloproyl. Enumerated Embodiment 31. The compound of any one of the previous Enumerated Embodiments, wherein at least one R₁₁ is selected from halogen, C₁-C₆ alkoxy, or C₁-C₆ alkyl. Enumerated Embodiment 32. The compound of any one of the previous Enumerated Embodiments, wherein at least one R11 is H. Enumerated Embodiment 33. The compound of any one of the previous Enumerated Embodiments, wherein at least one R₁₁ is fluoro. Enumerated Embodiment 34. The compound of any one of the previous Enumerated Embodiments, wherein at least one R₁₁ is C₁-C₆ alkoxy. Enumerated Embodiment 35. The compound of any one of the previous Enumerated Embodiments, wherein the compound is selected from: F F N N NH₂ NH₂ O O N N N N N N N N N H H N N O O

O N H N N N N O O O N N H

O N HN O N N N N H N O O N HN O O N N O N N H N O

O N HN O N N N N H N O O N HN O N N N N H N O O N HN O N N N N H N O

or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof. Enumerated Embodiment 36. A pharmaceutically acceptable composition comprising the compound according to any one of Enumerated Embodiments 1-35, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. Enumerated Embodiment 37. A method of inhibiting PAD4 in a subject or in a biological sample comprising the step of contacting the PAD4 with a compound according to any one of Enumerated Embodiments 1-35. Enumerated Embodiment 38. A method of treating a PAD4-mediated disease, disorder, or condition in a subject in need thereof comprising the step of administering to said subject the composition according to Enumerated Embodiment 36. Enumerated Embodiment 39. The method according to Enumerated Embodiment 38, wherein the PAD4-mediated disease, disorder, or condition is selected from the group consisting of acid-induced lung injury, acne (PAPA), acute lymphocytic leukemia, acute, respiratory distress syndrome, Addison’s disease, adrenal hyperplasia, adrenocortical insufficiency, ageing, AIDS, alcoholic hepatitis, alcoholic hepatitis, alcoholic liver disease, allergen induced asthma, allergic bronchopulmonary, aspergillosis, allergic conjunctivitis, alopecia, Alzheimer’s disease, amyloidosis, amyotropic lateral sclerosis, and weight loss, angina pectoris, angioedema, anhidrotic ecodermal dysplasia-ID, ankylosing spondylitis, anterior segment, inflammation, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, bee sting-induced inflammation, behcet’s disease, Behcet’s syndrome, Bells Palsey, berylliosis, Blau syndrome, bone pain, bronchiolitis, burns, bursitis, cancer, cardiac hypertrophy, carpal tunnel syndrome, catabolic disorders, cataracts, cerebral aneurysm, chemical irritant-induced inflammation, chorioretinitis, chronic heart failure, chronic lung disease of prematurity, chronic lymphocytic leukemia, chronic obstructive pulmonary disease, colitis, complex regional pain syndrome, connective tissue disease, corneal ulcer, crohn’s disease, cryopyrin-associated periodic syndromes, cyrptococcosis, cystic fibrosis, deficiency of the interleukin-1–receptor antagonist (DIRA), dermatitis, dermatitis endotoxemia, dermatomyositis, diffuse intrinsic pontine glioma, endometriosis, endotoxemia, epicondylitis, erythroblastopenia, familial amyloidotic polyneuropathy, familial cold urticarial, familial mediterranean fever, fetal growth retardation, glaucoma, glomerular disease, glomerular nephritis, gout, gouty arthritis, graft-versus-host disease, gut diseases, head injury, headache, hearing loss, heart disease, hemolytic anemia, Henoch-Scholein purpura, hepatitis, hereditary periodic fever syndrome, herpes zoster and simplex, HIV-1, Hodgkin’s disease, Huntington’s disease, hyaline membrane disease, hyperammonemia, hypercalcemia, hypercholesterolemia, hyperimmunoglobulinemia D with recurrent fever (HIDS), hypoplastic and other anemias, hypoplastic anemia, idiopathic thrombocytopenic purpura, incontinentia pigmenti, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, insect bite-induced inflammation, iritis, irritant-induced inflammation, ischemia/reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, kidney injury caused by parasitic infections, kidney injury caused by parasitic infections, kidney transplant rejection prophylaxis, leptospiriosis, leukemia, Loeffler’s syndrome, lung injury, lung injury, lupus, lupus, lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticaria deafness amyloidosis), multiple sclerosis, muscle wasting, muscular dystrophy, myasthenia gravis, myocarditis, mycosis fungiodes, mycosis fungoides, myelodysplastic syndrome, myositis, nasal sinusitis, necrotizing enterocolitis, neonatal onset multisystem inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathological diseases, non-allergen induced asthma, obesity, ocular allergy, optic neuritis, organ transplant, osterarthritis, otitis media, paget’s disease, pain, pancreatitis, Parkinson’s disease, pemphigus, pericarditis, periodic fever, periodontitis, peritoneal endometriosis, pertussis, pharyngitis and adenitis (PFAPA syndrome), plant irritant-induced inflammation, pneumonia, pneumonitis, pneumosysts infection, poison ivy/ urushiol oil-induced inflammation, polyarteritis nodosa, polychondritis, polycystic kidney disease, polymyositis, psoriasis, psoriasis, psoriasis, psoriasis, psychosocial stress diseases, pulmonary disease, pulmonary hypertension, pulmonayr fibrosis, pyoderma gangrenosum, pyogenic sterile arthritis, renal disease, retinal disease, rheumatic carditis, rheumatic disease, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cell, sickle cell anemia, silica-induced disease, Sjogren’s syndrome, skin diseases, sleep apnea, solid tumors, spinal cord injury, Stevens-Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, temporal arteritis, tenosynovitis, thrombocytopenia, thyroiditis, tissue transplant, TNF receptor associated periodic syndrome (TRAPS), toxoplasmosis, transplant, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticarial, uveitis, and Wegener’s granulomatosis. Enumerated Embodiment 40. The method according to Enumerated Embodiment 38, wherein the PAD4-mediated disease, disorder, or condition is selected from rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, and psoriasis. EQUIVALENTS [0291] While we have described a number of embodiments of this disclosure, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this disclosure. Therefore, it will be appreciated that the scope of this disclosure is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example. [0292] The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference. [0293] The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto.

Claims

CLAIMS 1. A compound of Formula I: (I), or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof, wherein: X₁ and X₂ are each independently CR₈ or N; Y is selected from -(CR9R10)p–, –O–(CR9R10)p-, –(CR9R10)p–O–(CH2)m-, –(CR9R10)p–O–(CH2)m– O–CH₂–, and –(CR₉R₁₀)_p–O–(CH₂)_m–O–; R₁ is independently –CH(NHR₇)-(C₁-C₃alkyl) or a 4- to 8-membered heterocycle containing at least one heteroatom selected from the group consisting of N, O, or S, wherein the alkyl or heterocycle is optionally substituted with one or more R11; R₂ is independently H, or C₁-C₄ alkyl; R3 is independently H, halogen, or C1-C4 alkyl; R4 is independently hydrogen, C1–C4 alkyl, or C1–C4 haloalkyl; R₅ and R₆ are independently selected from H, halogen, C₁–C₄ alkyl, C₁–C₄ alkoxy, C₁–C₄ haloalkyl, heteroaryl, and aryl; wherein the heteroaryl, or aryl is optionally substituted with one or more halogen or C1–C6 alkoxy; or R₅ and R₆ together with the intervening atoms, form a C₃-C₆ cycloalkyl or 4- to 8-membered heterocyclyl; or R5 , R6, and R9 together with the intervening and adjacent atoms, form a C3-C6 cycloalkyl, 4- to 8-membered heterocyclyl, a heteroaryl, or an aryl, wherein the cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more R₁₂; each R7 is independently selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl; each R8 is independently selected from H, halogen, C1–C4 alkyl, C1–C4 haloalkyl, and C1–C4 alkoxy; each R₉ is independently H, halogen, C₁-C₄ alkyl, or C₃-C₄ carbocyclyl; each R10 is independently H, halogen, or C1-C4 alkyl; each R11 is independently selected from H, halogen, C1–C6 alkyl, and C1–C6 alkoxy; each R₁₂ is independently selected from H, halogen, -OH, -NH₂, -CN, C₁–C₆ alkyl, C₁–C₄ alkoxy, C1–C4 haloalkoxy, C1–C4 haloalkyl, and C3–C4 cycloalkyl, 3- to 10-membered heterocyclyl, heteroaryl, and C6–C10 aryl; L is a bond or –CH₂–; m is an integer selected from 1, 2, and 3; and p is an integer selected from 2, 3, 4, 5, and 6.

2. The compound of claim 1, wherein the compound is of Formula (Ia): (Ia), wherein X3 is CH2, NH, O, or S, and r is an integer from 1 to 3.

3. The compound of claim 1 or 2, wherein the compound is of Formula (Ia-1) (Ia-1) , Formula (Ia-2) (Ia-2), Formula (Ia-3) (Ia-3), Formula (Ia-4)

(Ia-4), or Formula (Ia-5) (Ia-5),wherein X3 is NH, O, or S, and A is C₃-C₈ cycloalkyl, aryl, or heteroaryl. 4. The compound of claim 1, wherein the compound is of Formula (Ib): (Ib).

5. The compound of claim 1 or 4, wherein the compound is of Formula (Ib-1):

(Ib-6), wherein A is C₃-C₈ cycloalkyl, aryl or heteroaryl. 6. The compound of claim 1, wherein the compound is of Formula (Ic): (Ic).

7. The compound of claim 1 or 6, wherein the compound is of Formula (Ic-1):

(Ic-1), Formula (Ic-2): (Ic-2) Formula (Ic-3) (Ic-3), Formula (Ic-4) (Ic-4), or Formula (Ic-5): (Ic-5), wherein A is C₃-C₈ cycloalkyl, aryl, or heteroaryl.

8. The compound of claim 1, wherein the compound is of Formula (Id):

(Id), Formula (Ie): (Ie), or Formula (If): (If), wherein A is C3-C8 cycloalkyl, aryl, or heteroaryl; and r is an integer from 0 to 2.

9. The compound of any one of the previous claims, wherein R₂ is H or C₁–C₄ alkyl.

10. The compound of any one of the previous claims, wherein R₃ is H.

11. The compound of any one of the previous claims, wherein R4 is C1–C4 alkyl.

12. The compound of any one of the previous claims, wherein R7 is methyl or cyclopropyl.

13. The compound of any one of the previous claims, wherein at least one R₁₁ is selected from H, halogen, fluoro, C1-C6 alkoxy, or C1-C6 alkyl.

14. The compound of any one of the previous claims, wherein the compound is selected from: F F N N NH₂ NH₂ O O N N N N N N N N N H H N N O O

or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof.

15. A pharmaceutical composition comprising the compound according to any one of claims 1-14, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

16. A method of inhibiting PAD4 in a subject or in a biological sample comprising the step of contacting the PAD4 with a compound according to any one of claims 1-14.

17. A method of treating a PAD4-mediated disease, disorder, or condition in a subject in need thereof comprising the step of administering to said subject the pharmaceutical composition according to claim 15.

18. The method according to claim 17, wherein the PAD4-mediated disease, disorder, or condition is selected from the group consisting of acid-induced lung injury, acne (PAPA), acute lymphocytic leukemia, acute, respiratory distress syndrome, Addison’s disease, adrenal hyperplasia, adrenocortical insufficiency, ageing, AIDS, alcoholic hepatitis, alcoholic hepatitis, alcoholic liver disease, allergen induced asthma, allergic bronchopulmonary, aspergillosis, allergic conjunctivitis, alopecia, Alzheimer’s disease, amyloidosis, amyotropic lateral sclerosis, and weight loss, angina pectoris, angioedema, anhidrotic ecodermal dysplasia-ID, ankylosing spondylitis, anterior segment, inflammation, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, bee sting-induced inflammation, behcet’s disease, Behcet’s syndrome, Bells Palsey, berylliosis, Blau syndrome, bone pain, bronchiolitis, burns, bursitis, cancer, cardiac hypertrophy, carpal tunnel syndrome, catabolic disorders, cataracts, cerebral aneurysm, chemical irritant-induced inflammation, chorioretinitis, chronic heart failure, chronic lung disease of prematurity, chronic lymphocytic leukemia, chronic obstructive pulmonary disease, colitis, complex regional pain syndrome, connective tissue disease, corneal ulcer, crohn’s disease, cryopyrin-associated periodic syndromes, cyrptococcosis, cystic fibrosis, deficiency of the interleukin-1–receptor antagonist (DIRA), dermatitis, dermatitis endotoxemia, dermatomyositis, diffuse intrinsic pontine glioma, endometriosis, endotoxemia, epicondylitis, erythroblastopenia, familial amyloidotic polyneuropathy, familial cold urticarial, familial mediterranean fever, fetal growth retardation, glaucoma, glomerular disease, glomerular nephritis, gout, gouty arthritis, graft-versus-host disease, gut diseases, head injury, headache, hearing loss, heart disease, hemolytic anemia, Henoch-Scholein purpura, hepatitis, hereditary periodic fever syndrome, herpes zoster and simplex, HIV-1, Hodgkin’s disease, Huntington’s disease, hyaline membrane disease, hyperammonemia, hypercalcemia, hypercholesterolemia, hyperimmunoglobulinemia D with recurrent fever (HIDS), hypoplastic and other anemias, hypoplastic anemia, idiopathic thrombocytopenic purpura, incontinentia pigmenti, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, insect bite-induced inflammation, iritis, irritant-induced inflammation, ischemia/reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, kidney injury caused by parasitic infections, kidney injury caused by parasitic infections, kidney transplant rejection prophylaxis, leptospiriosis, leukemia, Loeffler’s syndrome, lung injury, lung injury, lupus, lupus, lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticaria deafness amyloidosis), multiple sclerosis, muscle wasting, muscular dystrophy, myasthenia gravis, myocarditis, mycosis fungiodes, mycosis fungoides, myelodysplastic syndrome, myositis, nasal sinusitis, necrotizing enterocolitis, neonatal onset multisystem inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathological diseases, non-allergen induced asthma, obesity, ocular allergy, optic neuritis, organ transplant, osterarthritis, otitis media, paget’s disease, pain, pancreatitis, Parkinson’s disease, pemphigus, pericarditis, periodic fever, periodontitis, peritoneal endometriosis, pertussis, pharyngitis and adenitis (PFAPA syndrome), plant irritant-induced inflammation, pneumonia, pneumonitis, pneumosysts infection, poison ivy/ urushiol oil-induced inflammation, polyarteritis nodosa, polychondritis, polycystic kidney disease, polymyositis, psoriasis, psoriasis, psoriasis, psoriasis, psychosocial stress diseases, pulmonary disease, pulmonary hypertension, pulmonayr fibrosis, pyoderma gangrenosum, pyogenic sterile arthritis, renal disease, retinal disease, rheumatic carditis, rheumatic disease, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cell, sickle cell anemia, silica-induced disease, Sjogren’s syndrome, skin diseases, sleep apnea, solid tumors, spinal cord injury, Stevens-Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, temporal arteritis, tenosynovitis, thrombocytopenia, thyroiditis, tissue transplant, TNF receptor associated periodic syndrome (TRAPS), toxoplasmosis, transplant, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticarial, uveitis, and Wegener’s granulomatosis.

19. The method according to claim 17, wherein the PAD4-mediated disease, disorder, or condition is selected from rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, and psoriasis.

20. The method according to claim 19, wherein the PAD4-mediated disease, disorder, or condition is rheumatoid arthritis.